Imidazoquinoline antithrombrogenic cardiotonic agents

ABSTRACT

Novel series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones of the Formula ##STR1## wherein R 1  is halogen, lower alkyl, lower alkoxy, trifluoromethyl; R 2  is hydrogen, halogen, lower alkyl, lower alkoxy; R 3  is hydrogen, halogen, lower alkyl, lower alkoxy; and R 4  is hydrogen or lower alkyl. The compounds are therapeutically useful as inhibitors of blood platelet aggregation and/or as cardiotonic agents.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation-in-part application of Ser. No. 726,869, filedApr. 25, 1985.

BACKGROUND OF THE INVENTION

This invention generally pertains to heterocyclic carbon compoundshaving drug and bio-affecting properties and to their preparation anduse. In particular, the invention is concerned with a series of new1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives which arephosphodiesterase inhibitors, blood platelet antiaggregators andcardiotonic agents.

As a structural class, applicants are aware of relatively few1,3-dihydro-2Himidazo[4,5-b]quinolin-2-ones with the following chemicalliterature illustrative of the art.

Kozak, et al., Bull. Intern. Acad. Polanaise, 1930A, 432-438 (Chem.Abs., 25, 5400) describes the unsubstituted compound1,3-dihydro-2Himidazo[4,5-b]quinolin-2-one of formula (1). ##STR2##

Musial, Roczniki Chem., 1951, 25, 46-52 (Chem. Abs., 1953, 47, 4885f)synthesized 1,3-derivatives of (1) as illustrated in formula (2).##STR3## R¹ =Br, NO₂, NH₂ R² =H, Br

Fryer, et al., J. Org. Chem., 1977, 42, 2212-2219 describes the3,7,9-trisubstituted compound of formula (3). ##STR4##

Reid, et al., Chem. Ber., 1956, 89, 2684-2687 describes the synthesis ofthe 1,3-diphenyl derivative of formula (4). ##STR5##

No pharmacological utility is taught for the1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one structures disclosed in theaforementioned references which are of a chemical nature.

Various derivatives of the tetrahydroimidazo[2,1-b]quinozolin-2-one (5)heterocycle have been studied for their platelet inhibition andcardiotonic properties. ##STR6## For example:

Beverung, Jr., et al., U.S. Pat. No. 3,932,407 disclose a series ofcompounds useful as blood platelet antiaggregative and/orantihypertensive and/or bronchodilator agents of thetetrahydroimidazo[2,1-b]quinazolin-2-one class. Anagrelide (6), aparticularly preferred member of the Beverung, Jr., et al. series, hasbeen studied extensively, e.g., J. S. Fleming, et al., New Drugs Annual:Cardiovascular Drugs, Raven Press, pages 277-294, New York (1983).##STR7##

Chodnekar, et al., U.S. Pat. No. 4,256,748 describes a series ofcompounds of the formula (7) as inhibitors of the aggregation of bloodplatelets and cardiotonic activity. ##STR8## Representative of theChodneker compounds are RO 14-2525 (R⁴ =CH₃, R³ =H, R² =6-CH₃, R¹ =7-Br)and RO 13-6438 (R⁴ =CH₃, R³ =H, R² =6-CH₃, R¹ =H).

SUMMARY OF THE INVENTION

In its broadest aspect, this invention is concerned with a new series of1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones having valuablepharmacological properties which makes them particularly useful ascardiotonic agents and/or inhibitors of phosphodiesterase and mammalianblood platelet aggregation. Formula I and Formula XII (infra.)illustrate the compounds of the invention and the ring numbering systemused herein. ##STR9## In the foregoing formula, R₁ is halogen, loweralkyl, lower alkoxy; R₂ is hydrogen, halogen, lower alkyl, lower alkoxy;and R₃ is hydrogen, halogen, lower alkyl, lower alkoxy. Anotherembodiment of the invention relates to pharmaceutically acceptablecompositions comprised of a Formula I or Formula XII (infra.) compoundcombined with at least one pharmaceutically acceptable excipient. Afurther embodiment of this invention relates to a method for inhibitingphosphodiesterase and blood platelet aggregation in a mammal whichcomprises administering a therapeutically effective amount of a compoundof Formula I or Formula XII (infra.) or a pharmaceutically acceptablesalt thereof to a mammal in need of such treatment. A still furtherembodiment of this invention relates to a method for increasing heartinotropic activity which comprises administering a therapeuticallyeffective amount of a compound of Formula I or Formula XII (infra.) or apharmaceutically acceptable salt thereof to a mammal in need of suchtreatment.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the instant invention comprise those of Formula I##STR10## wherein R₁ is halogen, lower alkyl, lower alkoxy;

R² is hydrogen, halogen, lower alkyl, lower alkoxy;

R₃ is hydrogen, halogen, lower alkyl, lower alkoxy;

or a pharmaceutically acceptable salt thereof.

As used herein, the term "halogen" or "halo" comprehends flourine,iodine, and most preferably bromine and chlorine; the term "lower alkyl"refers to a branched or unbranched saturated hydrocarbon chaincontaining from 1 to 4 carbon atoms; for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, tert.-butyl, and the like. The terms"alkyl of 1 to 4 carbon atoms" and "lower alkyl" are usedinterchangeably with specific terms represented by conventional symbols,i.e., Me═CH₃, Et═C₂ H₅, etc.

The term "lower alkoxy" comprehends ethers containing from 1 to 4 carbonatoms as defined for alkyl; such as methoxy, ethoxy, isopropoxy,tert.-butoxy, and the like.

According to the present invention, the compounds characterized byFormula I ##STR11## wherein R₁ is halogen, lower alkyl, lower alkoxy; R₂is hydrogen, halogen, lower alkyl, lower alkoxy; and R₃ is hydrogen,halogen, lower alkyl, lower alkoxy are obtained by a process comprising

(a) reducing a substituted hydantoin of Formula II ##STR12## wherein aand b are hydrogen or together are a covalent bond, R₁, R₂, and R₃ aredefined as above; and

(b) treating the reduced material with an oxidant such as iodine whenrequired.

The reduction of Formula II hydantoin intermediates is carried out byconventional chemical or catalytic methods. For instance, the Formula IIhydantoins can be chemically reduced by treatment with hydrogen iodideand red phosphorus according to the method of Kozak, et al., supra.Catalytic hydrogenation is particularly preferred and accomplished witha transition metal catalyst, preferably palladium-on-carbon, in anappropriate reaction inert solvent such as dimethylformamide. Reductionis carried out at room temperature and when hydrogen uptake isessentially complete, the reaction mixture is warmed and filtered oroptionally heated to about 100° C. for a 1 to 4 hour period beforefiltering. In some instances, residual material obtained byconcentrating the filtrate predominantly consists of the desired FormulaI product produced by facile cyclization and aratomization to the fusedquinoline ring system. In other instances, the residual materialpredominantly consists of the uncyclized Formula IIA amino hydantoin(wherein a and b, R₁, R₂, R₃ are as defined above) resulting fromreduction of the Formula II nitro hydantoin or the 4,5-dihydroquinolineintermediate of Formula IIB (wherein R₁, R₂ and R₃ are defined asabove). In other instances, the residual material predominantly consistsof a mixture of Formula IIA, IIB intermediates together with the desiredFormula I product. Without being bound by theory, the transformation ofa Formula II nitro-hydantoin to the Formula I product is thought toinvolve reduction of the nitro group and olefenic double bond to thecorresponding Formula IIA amine (wherein a and b are hydrogen). Ringcyclization follows or occurs simultaneously to the Formula I product orthe 1,3,9,9a-tetrahydroquinoline intermediate of Formula IIB which isaromatized by dehydrogenation. ##STR13## In those cases where thereaction is incomplete, the residual material is treated with an oxidantsuch as iodine in an alkanol solvent such as methanol ordimethylformamide and the like at reflux temperature. Under theseconditions, cyclization of Formula IIA amines to the Formula I productsor the Formula IIB tetrahydroquinoline intermediates with oxidation ofthe latter to the desired 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-onesof Formula I is effected. The Formula IIA and IIB compounds areconsidered part of the instant invention. When iodine is employed, theFormula I product is isolated in base form by sequentially treating thereaction mixture with aqueous sodium thiosulfate and alkali metalcarbonate such as sodium carbonate. Conversion of the base form topharmaceutically acceptable acid addition salts is carried out byconventional means.

The pharmaceutically acceptable acid addition salts of the instantinvention are those in which the anion does not contribute significantlyto the toxicity or pharmacological activity of the salt and, as such,they are the pharmacological equivalents of the bases of Formula I andFormula XII (infra.). They are generally preferred for medical usage. Insome instances, they have physical properties which makes them moredesirable for pharmaceutical formulation purposes such as solubility,lack of hygroscopicity, compressibility with respect to tablet formationand compatibility with other ingredients with which the substance may beused for pharmaceutical purposes. As stated above, the salts areconventionally prepared, for instance by treating a Formula I forFormula XII (infra.) base with the selected acid preferably in solution.They may also be made by metathesis or treatment with an ion exchangeresin under conditions in which the anion of one salt of the substanceof the Formula I is replaced by another anion under conditions whichallow for separation of the desired species such as by precipitationfrom solution or extraction into a solvent, or elution from or retentionon an ion exchange resin. Pharmaceutically acceptable acids for thepurposes of salt formation of the substances of Formula I includehydrochloric, hydrobromic, hydroiodic, citric, acetic, propionic,benzoic, mandelic, sulfuric, phosphoric, nitric, mucic, isethionic,methanesulfonic, ethanesulfonic, p-toluene sulfonic, palmitic,heptanoic, and others.

The Formula II hydantoins wherein a and b are hydrogen employed in theprocess for preparing the instant compounds can be prepared according toprocedures described by Connors, et al., J. Chem. Soc., 2994-3007 (1960)illustrated in the following reaction scheme. ##STR14## In Method A, the"X" symbol in Formula III intermediates represents a suitable leavinggroup such as mesylate, tosylate, phosphate, sulfate and halogen,preferably chlorine or bromine. Such compounds are commerciallyavailable or can be obtained by methods known to the art. For example,the Formula III intermediate 2,3-dimethyl-6-nitrobenzylchloride can beprepared from 2,3-dimethyl-6-nitroaniline by conventional methodsaccording to the following scheme. ##STR15## The2,3-dimethyl-6-nitrobenzyl alcohol precursor to the benzyl chloride(III) can readily be esterified to further provide Formula IIIintermediates such as the mesylate, tosylate, phosphate, sulfate and thelike. In step 1 of Method A, benzyl-X starting material (III), e.g.,orthonitro-R₁,R₂,R₃ -substituted benzyl chloride, is condensed withdiethyl acetamidomalonate in a reaction inert solvent such as ethanol,methanol, n-propanol, acetonitrile, dimethylformamide in the presence ofa suitable alkali metal base such as sodium ethoxide, sodium hydroxide,sodium carbonate and the like, at temperatures ranging from 50° to 150°C. to provide the diethyl-alpha-acetamido-2-nitrobenzylmalonateintermediates of Formula IV. The reaction period varies to some extentdepending on solvent, alkali metal salt and temperature selected. In thecase of sodium ethoxide in ethanol, the reaction is carried out atreflux temperature for a period of 1 to 24 hours. In step 2, thephenylalanines of Formula V are obtained by refluxing the benzylmalonateesters (IV) in a strong acid such as 50% hydrochloric acid. In step 3,the phenylalanine (V) is treated with potassium cyanate at about 100° C.and the mixture acidified to provide the aminocarbonyl phenylalanineFormula VI intermediates. In step 4, the Formula VI intermediates arecyclized to the substituted hydantoins of Formula II wherein a and b arehydrogen. Cyclization to the hydantoin intermediates is effected underacid conditions, for instance with 50% hydrochloric acid at 100° C. orby refluxing in ethanol with hydrogen chloride.

Formula II (wherein a and b are hydrogen) hydantoins can also beobtained according to the method illustrated in the following reactionscheme. ##STR16## Method B involves alkylating the sodium salt of ethylhydantoin-5-carboxylate with a Formula III benzyl intermediate followedby hydrolytic decarboxylation of the alkylated intermediate. In Step 1,the Formula III benzyl intermediate is reacted with ethylsodiohydantoin-5-carboxylate (VII) in a reaction inert solvent. Suitablesolvents include alcohols such as methanol, ethanol, propanol,isopropanol and the like as well as other solvents generally used inalkylating reaction such as acetonitrile, dimethylformamide and thelike. In addition to the sodium salt of the hydantoin ester which ispreferred, other strong alkali salts such as potassium and lithium areoperable. Conversion of the Formula VIII hydantoin-5-carboxylateintermediates to the Formula II hydantoins is effected underconventional hydrolysis and decarboxylation conditions such as heatingthe hydantoin of Formula VIII with 50% hydrochloric acid.

The Formula II hydantoins wherein a and b together represent a covalentbond can be prepared according to procedures described by Billek,Monatsh, 1961, 92, 352-360 (Chem. Abs., 1962, 56, 394b) illustrated inthe following reaction scheme. ##STR17## Method C involves condensationof a substituted benzaldehyde of Formula IX with hydantoin (X) in thepresence of fused sodium acetate in acetic anhydride at elevatedtemperatures (e.g., 100°-160° C.). Hydrolysis of the N-acetylintermediate (XI) obtained in Step 1 is conventionally carried out withan alkali metal hydroxide such as sodium hydroxide to provide thebenzylidine hydantoin of Formula II wherein a and b together form acovalent bond.

As stated above, the Formula I compounds or pharmaceutically acceptablesalts thereof have pharmacological properties which make themparticularly useful as phosphodiesterase inhibitors, blood plateletantiaggregators and/or cardiotonic agents. Regarding the latter,compounds of the invention selectively strengthen myocardial contractionforce by which the heart ventricles pump blood into the periphery. Thus,the instant compounds are useful in the curative or prophylactictreatment of cardiac conditions such as myocardial failure where anincrease in positive inotropic activity is desirable. Preferredcompounds increase contractile force without unduly increasing heartrate.

Platelet aggregation is considered part of a complex physiologicalmechanism for formation of a thrombus in the vascular system.Thromboembolic phenomena, i.e., the formation of thrombi, are involvedin hemostasis and a number of diseased states in mammals includingthrombophlebitis, phlebothrombosis, cerebral thrombosis, coronarythrombosis and retinal vessel thrombosis. An increase in propensity forplatelet aggregation, sometimes referred to as platelet adhesiveness, isobserved following parturition, surgical operations such as coronaryartery bypass surgery, organ transplant, angioplasty, prosthetic heartvalve implants to name a few; and in ischaemic heart disease,atherosclerosis, multiple sclerosis, intracranial tumors,thromboembolism, and hyperlipemia; refer to A. Poplawski, et al., J.Atherosclerosis Research, 8, 721 (1968). Thus, the compounds of theinvention which have antithrombogenic (inhibit blood plateletaggregation) and phosphodiesterase inhibition properties are useful inprevention or treatment of conditions involving platelet aggregation andthrombosis such as the above. Literature relating to prophylactic andtherapeutic activities of phosphodiesterase inhibiting compounds includethe following: S. M. Amer, "Cyclic Nucleotides as Targets For DrugDesign," Advances in Drug Research, Vol. 12, 1977, Academic Press,London, pp 1-38; I. Weinryh, et al., J. Pharm. Sci., pp 1556-1567(1972); S. M. Amer, et al., J. Pharm. Sci., Vol. 64, pp 1-37 (1975); andD. N. Harris, et al., Enzyme Inhibitors As Drugs, McMillan & Co., Ed--M.Standler, pp 127-146, (1980). The instant compounds are considered tohave antimetastatic potential in view of their platelet inhibitionproperties.

The pharmacological properties of the instant compounds can bedemonstrated by conventional in vitro and in vivo biological tests suchas the following.

IN VITRO INHIBITION OF PLATELET AGGREGATION

The aggregometer method of Born (1), as modified by Mustard, et al. (2)was used to assess the in vitro activity of the various compounds as toinhibition of adenosine diphosphate (ADP) and collagen-induced plateletaggregation. Platelet rich plasma (PRP) was separated by centrifugationfrom citrated (3.8 percent) rabbit blood. ADP in final concentration of0.5 mcg/ml or 0.05 ml of a collagen suspension prepared according to themethod described by Evans, et al. (3) was used to induce aggregation.The various compounds tested were dissolved in dimethylsulfoxide (DMSO)so that 5 mcl added to the platelet rich plasma would yield the desiredtest concentration. Vehicle control trials were done and compared withaggregation induced in platelet rich plasma containing variousconcentrations of the test compounds. Dose response curves were obtainedand Effective Concentration (EC50) values calculated. In this test, theEC₅₀ values for dipyrimidol, a clinically useful antithrombogenic agent,are >512 mcg/ml vs. ADP and 245 mcg/ml vs. collagen. Results are givenin Table I hereinafter for various Formula I and XII (infra.) compounds.

1. Born, G. V. R., J. Physiol., London, 162, 67P (1962).

2. Mustard, J. F., Hegardt, B. Rowsell, H. C. and MacMillan, R. L., J.Lab. Clin. Med., 64, 548 (1964).

3. Evans, G., Marian M. C., Packham, M. A., Nishizawa, E. E., Mustard,J. F. and Murphy, E. A., J. Exp. Med., 128, 877 (1968).

INHIBITION OF PLATELET AGGREGATION FOLLOWING ORAL ADMINISTRATION

This test is sometimes referred to in the art as an Ex vivo method andwas initially described by Fleming, et al., Arch. Int. Pharmacodyn.Ther., 199, 164 (1972). Briefly, the assay is essentially carried out asfollows.

Aggregometry is performed in vitro as previously described on plateletrich plasma samples obtained from rats dosed with either test compoundsor the vehicle. In all cases, activity is determined 2 hours after thedrug is administered orally at various doses by gavage as a suspensionin 0.9% water plus a few drops of Tween 20. Drug activity is expressedas ED₅₀ 's (that dose required to inhibit the induced aggregation by50%) calculated from results obtained from groups of 10 animals treatedwith various doses of test compounds in comparison to separate controlgroups.

In this test, the ED₅₀ of dipyridamole is greater than 100 mg/kg andanagrelide is 4.9 mg/kg. Results are given in Table I hereinafter forvarious Formula I and Formula XII (infra.) compounds.

INHIBITION OF CYCLIC AMP PHOSPHODIESTERASE

This assay is carried out essentially as described by Thompson, et al.,Methods in Enzymology, 38, 205-212 (1974). Briefly, tritium labeledcyclic adenosine monophosphate (cAMP) is incubated with aphosphodiesterase (PDE) enzynme obtained from human platelets whichconverts a portion of the cAMP to 5'AMP in culture tubes. This reactionis terminated by submerging the tubes in a boiling water bath afterwhich they are placed on ice and an aliquot of snake venom is added toeach tube. This, during a second incubation, converts the 5'AMP toadenosine. Ion exchange resin is added to bind the remaining cyclic AMP.The tubes are centrifuged to sediment the resin and a portion of theclear supernatent (which contains radioactive adenosine) is counted in aliquid scintillation counter. The cAMP phosphodiesterase inhibitionactivity of a test agent is determined by pre-incubating the PDE enzymepreparation with the test agent. Dose response values are obtained andactivity of the test agent reported as the molar (M) concentration ofthe test agent inhibiting 50% of the PDE activity (IC₅₀ s). In thistest, the IC₅₀ value of milrinone, a known inotropic agent, is 2×10⁻⁷molar. Results are given in Table I hereinafter for various Formula Iand Formula XII (infra.) compounds.

IN VITRO INOTROPIC ACTIVITY

The basic assay is a modification of that described by Anderson, DrugDevelopment Research, 3, 443-457 (1983). Briefly, guinea pigs aresacrificed by cervical disclocation and the heart rapidly exposed. Silkthread ties are placed on the left atria and these are removed from theanimal and mounted in tissue baths where they are electrically driven.After an initial equilibration period, the atria are treated withpropanolol at a concentration of 10⁻⁵ Molar (M). This depresses theirnative force of contraction but also renders them more sensitive to thepositive inotropic effects of phosphodiesterase inhibitors. The abilityof drugs to increase the force of contraction of the atria is assessed.Dose response curves of test compounds are obtained and reported as apercent of the propanolol control value. When desired, the chronotropicresponse of right atria which beat spontaneously can also be assessed.Results are given in Table II hereinafter for various Formula I andFormula XII (infra.) compounds.

IN VIVO INOTROPIC ACTIVITY

This test is carried out in ferrets as follows.

Fasted anesthetized ferrets are instrumented to study hemodynamicparameters as well as right ventricular contractile force using aWalton-Brodie open strain guage arch. Drugs are administeredintraduodenally as solutions in DMSO (1 mL or less) and effects onmyocardial contractile force and other parameters are monitored for 60minutes after dosing. Changes in contractile force in response to drugtreatment are expressed in terms of percent change from predose control.

In this test, milrinone produces a 52% increase in RVCF at 3 mg/kg.Results are given in Table II hereinafter for various Formula I andFormula XII (infra.) compounds.

                  TABLE I                                                         ______________________________________                                        Inhibition of Platelet Aggregation                                            and cAMP Phosphodiesterase                                                         Platelet Inhibition        cAMP                                          Ex-  In Vitro - Rabbit PRP                                                                         Ex Vivo    Phosphodiesterase                             am-  EC.sub.50 (mcg/ml)                                                                            vs. ADP    Human Platelets                               ple.sup.a                                                                          vs. ADP  vs. collagen                                                                             ED.sub.50 (mg/kg)                                                                      IC.sub.50 (M)                               ______________________________________                                         1   0.8      0.2        12.6     3 × 10.sup.-7                          2   0.75     0.08       18.9     3 × 10.sup.-7                          3   0.08     0.03       13.3     3 × 10.sup.-9                          4   0.18     0.06       12.2     5 × 10.sup.-8                          5   0.4      0.125      14.9     5 × 10.sup.-8                          6   0.5      0.1        18.3     3 × 10.sup.-8                          7   0.1      0.03       3.2      1.5 × 10.sup.-9                        8   0.6      0.3        6.8      5 × 10.sup.-8                          9   0.15     0.1        8.4      1 × 10.sup.-7                         10   0.1      0.1        7.3      4 × 10.sup.-8                         11   0.11     0.09       32       2 × 10.sup.- 8                        12   0.04     0.02       5        2 × 10.sup.-8                         13   0.13     0.08                6 × 10.sup.-9                         14   0.96     0.94       10.sup.b 5 × 10.sup.-9                         22   0.3      0.2                 1 × 10.sup.-7                         23   0.15     0.1        8.2      8 × 10.sup.-9                         24   0.25     0.13                2 × 10.sup.-6                         25   0.4      0.7        >10      3 × 10.sup.-7                         26   10       10                  7 × 10.sup.-6                         27   7        7                   3 × 10.sup.-6                         28   4        3                   2 × 10.sup.-6                         29   7        3                   1 × 10.sup.-6                         20-3 0.05     0.03                1 × 10.sup.-7                         35   0.1      0.04       >10      3 × 10.sup.-8                         36   20       12                  9 × 11.sup.-6                         ______________________________________                                         .sup.a Refer to examples below for compound identification.                   .sup.b 33% inhibition.                                                   

                  TABLE II                                                        ______________________________________                                        Inotropic Activity                                                                                   In Vivo - Ferret                                                 In Vitro     % Change RVCF                                          Example.sup.a                                                                           Guinea Pig Atria.sup.b                                                                     3 mg/kg, i.d..sup.c                                    ______________________________________                                        1         ++           -6 ± 6                                              2         +            .sup. 25 ± 3.sup.d                                  3         ++++         27 ± 2                                              4         ++           -8 ± 1.sup.e                                        5         +             2 ± 2                                              6         0            -12 ± 2.sup.f                                       7         ++++         24 ± 2                                              8         0             18 ± 13                                            9         +            17 ± 9                                              10        0            .sup. 21 ± 3.sup.g                                  11        0            6                                                      12        ++           11 ± 4                                              20-3                   .sup. 15 ± 4.sup.h                                  ______________________________________                                         .sup.a Refer to Examples below for compound identification.                   .sup.b Activity  increase in contractile force                                0  Not significant at 10.sup.-4 M                                             +   50% increase at 10.sup.-4 to 10.sup.-5 M                                  ++ 50% increase at 10.sup.-5 to 10.sup.-6 M                                   +++ 50% increase at 10.sup.-6 to 10.sup.-7 M                                  ++++ 50% increase below 10.sup.-7 M                                           .sup.c Mean ± standard error when number (n) more than 1.                  .sup.d 8 ± 6 at 10 mg/kg                                                   .sup.e 2 at 10 mg/kg                                                          .sup.f 12 ± 12 at 10 mg/kg                                                 .sup.g 14 ± 8 at 10 mg/kg                                                  .sup.h 30 ± 5 at 0.3 mg/kg                                            

As stated above, one aspect of this invention relates to a therapeuticmethod for inhibiting phosphodiesterase and blood platelet aggregationin a mammal which comprises administering a therapeutically effectiveamount of a compound of Formula I or Formula XII (Infra.) or apharmaceutically acceptable salt thereof to a mammal in need of suchtreatment. Another aspect of this invention as stated above relates to atherapeutic method for increasing heart inotropic activity whichcomprises administering to a warm-blooded animal, including man, in needof such treatment a therapeutically effective amount of a compound ofFormula I or Formula XII (infra.), preferably a compound selected fromthe group consisting of

7-fluoro-1,3-dihydro-2Himidazo[4,5-b]quinolin-2-one

8-methyl-1,3-dihydro-2Himidazo[4,5-b]quinolin-2-one

1,3-dihydro-7,8-dimethyl-2Himidazo[4,5-b]quinolin-2-one

1,3-dihydro-8-chloro-7-methyl-2Himidazo[4,5-b]quinolin-2-one

8-methyl-1,3,9,9a-tetrahydro-2Himidazo[4,5-b]quinolin-2-one

The dosage employed in the instant therapeutic methods will vary withthe form of administration, the particular compound chosen, the subjectbeing tested and the effect desired. Suitable effective doses in animalsrange from 0.5-30 mg/kg body weight orally and from 0.05-10 mg/kg bodyweight parenterally (generally characterized as subcutaneous,intramuscular, and intravenous injection). It is contemplated that theeffective unit dose in man will range from 0.1 to 30 mg. and preferablyfrom 0.5 to 20 mg. administered one to three times a day. In accordancewith conventional clinical practice, the effective dose can bedetermined by administering a Formula I compound at a dosagesubstantially less than the dose of the compound which is thought to beeffective and then increasing the dosage in small increments until thedesired effect is achieved.

In carrying out the instant therapeutic methods, the active ingredientof Formula I and Formula XII (infra.) and pharmaceutically acceptableacid addition salts thereof are preferably administered with apharmaceutically acceptable carrier and such compositions constitutepart of the instant invention. Suitable dosage forms for oral use aretablets, dispersible powders, granules, capsules, syrups and elixirs.Examples of parenteral forms are solutions, suspensions, dispersions,emulsions, and the like. The compositions for oral use may contain oneor more conventional adjuvants, such as sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide acomposition of suitable pharmaceutical elegance. Tablets may contain theactive ingredient in admixture with conventional pharmaceuticalacceptable excipients including inert diluents such as calciumcarbonate, sodium carbonate, lactose and talc; granulating anddisintegrating agents such as starch and alginic acid; binding agentssuch as starch, gelatin and acacia and lubricating agents such asmagnesium stearate, stearic acid and talc. The tablets may be uncoatedor coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Similarly, suspension, syrups and elixers may contain theactive ingredient in admixture with any of the conventional excipientsutilized for the preparation of such compositions such as suspendingagents (e.g., methylcellulose, tragacanth, and sodium alginate), wettingagents (e.g., lecithin, polyoxyethylene stearate) and preservatives suchas ethyl-p-hydroxybenzoate. Capsules may contain the active ingredientalone or admixed with an inert solid diluent such as calcium carbonate,calcium phosphate and kaolin. The injectible compositions are formulatedas known in the art and may contain appropriate dispersing or wettingagents and suspending agents identical or similar to those mentionedabove.

The following examples are given by way of illustration and are not tobe construed as limiting the invention in any way inasmuch as manyvariations of the invention are possible within the spirit of theinvention. All temperatures are degrees centrigrade and melting pointstaken with a Thomas Hoover capillary apparatus are uncorrected.Conventional abbreviations are employed in reporting Nuclear MagneticResonance (NMR) spectral data with tetramethylsilane as internalreference and chemical shift data values in parts per million.

EXAMPLE 1 8-Chloro-1,3-dihydro-2H-imidazo[4.5-b]quinolin-2-one ##STR18##

5-[(2-Chloro-6-nitrophenyl)methyl]-2,4-imidazolidinedione (2 g, 7.4mmol) in dimethylformamide (40 mL) was hydrogenated over 10% palladiumon charcoal (0.2 g) at 60 psi until hydrogen uptake ceased. The reactionmixture was heated on a steam bath for 2 hours, filtered through a padof infusorial earth and concentrated in vacuo to give a solid.Crystallization from methanol gave hydrated8-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (1.20 g, 56%),m.p. >360° C.

Anal. Calcd. for C₁₀ H₆ ClN₃ O.0.1H₂ O: C, 52.24; H, 2.82; N, 18.98; Cl,16.01; H₂ O, 0.81. Found: C, 54.18; H, 2.93; N, 18.93; Cl, 15.76; H₂ O,0.75.

NMR (DMSO-d₆): 7.44 to 7.65 (2, m); 7.69 (1, s); 7.80 (1, dd, 3 Hz, 6Hz); 11.18 (1, bs); 11.70 (1, bs).

EXAMPLE 2 7-Fluoro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one ##STR19##

5-[(5-Fluoro-2-nitrophenyl)methyl]-2,4-imidazolidinedione (6 g, 23 mmol)in dimethylformamide (120 mL) was hydrogenated over 10% palladium oncharcoal (0.6 g) at 60 psi until hydrogen uptake ceased. The reactionmixture was heated on a steam bath for 2.5 hours, filtered through a padof infusorial earth and concentrated in vacuo to give a solid which wassuspended in boiling methanol (750 mL). After 18 hours, the hot mixturewas filtered and solvent evaporated to leave a solid which was dissolvedin boiling methanol (500 mL) and iodine (2.0 g, 7.9 mmol) added in 2equal portions. After 15 minutes, the solvent was evaporated and theresidue treated with a solution of sodium thiosulfate (10 g) in water(100 mL) and sodium carbonate (5 g) in water (50 mL). A sandy brownsolid (2.80 g) was filtered off and dissolved in dimethyl sulfoxide (30mL). Addition of dichloromethane precipitated 7-(fluoro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one as a hydratedichloromethane solvent dimethyl sulfoxide solvate (2.18 g, 45%)m.p. >360° C.

Anal. Calcd. for C₆ H₆ FN₃ O.0.2H₂ O0.05CH₂ Cl₂.0.05C₂ H₆ OS: C, 56.72;H, 3.19; N, 19.55; H₂ O, 1.68. Found: C, 57.01; H, 3.09; N, 19.24; H₂ O,1.66.

NMR (DMSO-d₆): 2.60 (bs, ##STR20## 5.74 (s, CH₂ CH₂); 7.20-7.95 (4, m);11.30 (2, bs).

EXAMPLE 3 8-Methyl-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one ##STR21##

5-[(2-Methyl-6-nitrophenyl)methyl]-2,4-imidazolidinedione (5 g, 20 mmol)in dimethylformamide (200 mL) was hydrogenated over 10% palladium oncharcoal (0.5 g) at 60 psi until hydrogen uptake ceased. The reactionmixture was heated on a steam bath for 2 hours, filtered through a plugof infursorial earth and the solvent evaporated. The residual solid wassuspended in boiling methanol and iodine (4 g, 15 mmol) added in fourequal portions over 10 minutes. The mixture was refluxed 10 minutes,concentrated in vacuo and the residue treated with a solution of sodiumthiosulfate (45 g) in water (150 mL) and a solution of sodium carbonate(15 g) in water (150 mL). The insoluble solid (4.75 g) was filtered offand dissolved in 10% hydrogen chloride in methanol. Addition of etherprecipitated 8-methyl-1,3-dihdyro-2H-imidazo[4,5-b]quinolin-2-one as ahydrochloride hydrate (3.38 g, 71%), m.p. 350° -355° C. (dec).

Anal. Calcd. for C₁₁ H₉ N₃ O.HCl.0.35H₂ O: C, 54.60; H, 4.46; N, 17.37;Cl, 14.61; H₂ O, 2.61. Found: C, 54.30; H, 4.15; N, 17.49; Cl, 14.54; H₂O, 0.38.

NMR (DMSO-d₆): 2.62 (3, s); 7.35 (1, d, 8 Hz); 7.54 (1, d, 8 Hz); 7.80(1, s); 7.83 (1, d, 8 Hz); 9.72 (1, bs); 11.70 (1, bs).

EXAMPLE 4 7-Methyl-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one ##STR22##

5-[(5-Methyl-2-nitrophenyl)methyl]-2,4-imidazolidinedione (5 g, 20 mmol)in dimethylformamide (200 mL) was hydrogenated over 10% palladium oncharcoal (0.5 g) at 60 psi until hydrogen uptake ceased. The reactionmixture was heated on a steam bath for 2 hours, filtered throughinfusorial earth and concentrated in vacuo. The residual solid wastreated with boiling methanol (300 mL) and iodine (4 g, 15 mmol) addedin 2 equal portions over 10 minutes. Reflux was continued for a further25 minutes before the solvent was evaporated and the residue treatedwith a solution of sodium thiosulfate (17 g) in water (170 mL) and asolution of sodium carbonate (10 g) in water (100 mL). A light brownsolid was filtered off (4.09 g) and dissolved in 10% hydrogen chloridein methanol. Addition of ether precipitated7-methyl-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one as a hydrochloridehydrate (3.60 g, 74%) m.p. >360°.

Anal. Calcd. for C₁₁ H₉ N₃ O.HCl.0.3H₂ O: C, 54.81; H, 4.43; N, 17.43;Cl, 14.71; H₂ O, 2.24. Found: C, 55.15; H, 4.56; N, 17.16; Cl, 14.03; H₂O, 0.69.

NMR (DMSO-d₆): 2.45 (3, s); 7.44 (1, d, 8 Hz); 7.75 (2, s); 7.90 (1, d,8 Hz); 11.00 (1, bs); 11.62 (1, bs).

EXAMPLE 5 7-Chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one ##STR23##

5-[(5-Chloro-2-nitrophenyl)methyl]-2,4-imidazolidinedione (3 g. 11.1mmol) in dimethylformamide (60 mL) was hydrogenated over 10% palladiumon charcoal (0.3 g) at 60 psi until hydrogen uptake ceased. The reactionmixture was heated on a steam bath for 2 hours, filtered throughinfusorial earth and concentrated to about 10 mL. Addition ofdichloromethane furnished hydrated7-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (1.22 g, 50%),m.p. >360° C.

Anal. Calcd. for C₁₀ H₆ ClN₃ O0.1H₂ O: C, 54.24; H, 2.82; N, 18.98; Cl,16.01; H₂ O, 0.81. Found: C, 54.36; H, 2.83; N, 18.88; Cl, 15.29; H₂ O,0.52.

NMR (DMSO-d₆): 7.46 (1, dd, 2 Hz, 9 Hz); 7.59 (1, s); 7.79 (1, d, 9 Hz);7.99 (1, d, 2 Hz); 11.10 (1, bs); 11.50 (1, bs).

EXAMPLE 6 1,3-Dihydro-6,7-dimethyl-2H-imidazo[4,5-b]quinolin-2-one##STR24##

A solution of5-[(4,5-dimethyl-2-nitrophenyl)methyl]-2,4-imidazolidinedione (3 g, 11.4mmol) in dimethylformamide (100 mL) was hydrogenated over 10% palladiumon charcoal (0.3 g) until hydrogen uptake ceased. The reaction mixturewas heated on a steam bath for 3 hours before filtering throughinfusorial earth. Evaporation of the solvent afforded an oil which wasdissolved in boiling methanol (150 mL) and treated with iodine (2 g, 7.5mmol) in 2 equal portions over 15 minutes. After a further 15 minutes atreflux the solvent was evaporated and a solution of sodium carbonate (9g) and sodium thiosulfate (9 g) in water (180 mL) added. A pale yellowsolid was filtered off and dissolved in 10% hydrogen chloride inmethanol. The solvent was evaporated and the residue crystallized frommethanol to give1,3-dihydro-6,7-dimethyl-2H-imidazo[4,5-b]quinolin-2-one as ahydrochloride hydrate (1.04 g, 47%), m.p. >360° C.

Anal. Calcd. for C₁₂ H₁₁ N₃ O.HCl.0.15H₂ O: C, 57.10; H, 4.91; N, 16.65;H₂ O, 1.07. Found: C, 57.04; H, 5.01; N, 16.57; H₂ O, 1.02.

NMR (DMSO-d₆): 2.36 (3, s); 2.39 (3, s); 7.70 (3, s).

EXAMPLE 7 1,3-Dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one##STR25## (a) 1,3-Dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-onehydrochloride

5-[(2,3-Dimethyl-6-nitrophenyl)methyl]-2,4-imidazolidinedione (2.15 g,8.2 mmol) in dimethylformamide (30 mL) was hydrogenated over 10%palladium on charcoal (0.2 g) at 55 psi. After 4 hours, 10% palladium oncharcoal (0.2 g) was added and hydrogenation continued. After 18 hours,the reaction mixture was heated on a steam bath for 1.5 hours, cooled,filtered through infusorial earth and the solvent evaporated. Theresidual solid was suspended in boiling methanol (100 mL) and treatedwith iodine (1 g). After 30 minutes the reaction mixture wasconcentrated to about 30 mL and a solution of sodium thiosulfate (10 g)and sodium carbonate (10 g) in water (100 mL) added. A brown solid wasfiltered off, washed with water and methanol and treated with 10%hydrogen chloride in methanol. The insoluble brown solid was suspendedin boiling methanol and filtered to give1,3-dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one as ahydrochloride hydrate (1.0 g, 49%) m.p.>360° C.

Anal. Calcd. for C₁₂ H₁₁ N₃ O.HCl.0.2H₂ O: C, 56.90; H, 4.93; N, 16.59;H₂ O, 1.42. Found: C, 57.01; H, 4.89; N, 16.33; H₂ O, 1.07.

NMR (DMSO-d₆ /CF₃ CO₂ H): 2.41 (3, s); 2.52 (3, s); 7.59 (2, AB quartet,9 Hz); 7.89 (1, s); 11/50 (3, bs).

(b) 1,3-Dihydro-7,8-dimethyl-2H-imidazo[4.5-b]quinolin-2-one hydrate

5-[(2,3-Dimethyl-6-nitrophenyl)-methyl]-2,4-imidazolidine (40.18 g, 0.15mole) in dimethylformamide (500 mL) was hydrogenated over 10% palladiumon charcoal (6 g) at 60 psi. After 66 hours, the mixture was dilutedwith dimethylformamide (300 mL), warmed to dissolve some precipitatedmaterial, treated with charcoal, filtered through infusorial earth andconcentrated. Residual material was suspended in boiling methanol (2liters) and iodine (38.7 g, 0.15 mole) added portionwise over a periodof 30 minutes. Reflux was continued for a further 10 minutes, themixture concentrated to approximately 400 mL and a solution of sodiumthiosulfate (60 g) and sodium carbonate (60 g) in water (600 mL) added.The precipitate was collected, washed with water and methanol and thentriturated with water (500 mL). The triturated solid was collected,suspended in boiling methanol (200 mL), cooling and filtered to affordhydrated 1,3-dihydro-7,8-dimethyl-2H-imidazo[4.5-b]quinolin-2-one (29.44g, 88%), m.p.>310° C.

Anal. Calcd. for C₁₂ H₁₁ N₃ O.0.2H₂ O: C, 66.47; H, 5.30; N, 19.38; H₂O, 1.66. Found: C, 66.14; H, 5.12; N, 19.32; H₂ O, 1.0.

NMR (DMSO-d₆): 2.41 (3, s); 2.49 (3, s); 7.45 (2, AB quartet, 9 Hz);7.62 (1, s); 10.90 (1, s); 11.30 (1, bs).

EXAMPLE 8 1,3-Dihydro-7-chloro-6-methyl-2H-imidazo[4.5-b]quinolin-2-one##STR26##

5-[(5-Chloro-4-methyl-2-nitrophenyl)methyl]-2,4-imidazolidinedione (2 g,7 mmol) in dimethylformamide (30 mL) was hydrogenated over 5% platinumon carbon (0.4 g) at 55 psi until hydrogen uptake ceased. The mixturewas heated on a steam bath for two hours, concentrated in vacuo and theresidue treated with hot (90° C.) dimethyl sulfoxide. Filtration throughinfusorial earth and evaporation of the solvent afforded a solid whichwas washed with ether and suspended in boiling methanol. Filtration gave1,3-dihydro-7-chloro-6-methyl-2Himidazo[4,5-b]quinolin-2-one (1.40 g,84%) m.p.>360° C.

Anal. Calcd. for C₁₁ H₈ ClN₃ O: C, 56.55; H, 3.45; N, 17.98; Cl, 15.17.Found: C, 56.34; H, 3.52; N, 17.71; Cl, 14.83.

NMR (DMSO-d₆): 2.45 (3, s); 7.55 (1, s); 7.72 (1, s); 7.98 (1, s).

EXAMPLE 9 1,3-Dihydro-8-methoxy-2H-imidazo[4,5-b]quinolin-2-one##STR27##

This compound was prepared analogous to Example 7(b) from5-[(2-methoxy-6-nitrophenyl)methyl]-2,4-imidazolidinedione. The titleproduct is obtained as a hydrate (91%), m.p.>300° C.

Anal. Calcd. for C₁₁ H₉ N₃ O₂.0.25H₂ O: C, 60.13; H, 4.36; N, 19.13; H₂O, 2.05. Found: C, 59.85; H, 4.12; N, 18.78; H₂ O, 1.26.

NMR (DMSO-d₆): 3.97 (3, s); 6.88 (1, dd, 4 Hz, 5 Hz); 7.35-7.50 (2, m);7.71 (1, s); 10.98 (1, bs); 11.45 (1, bs).

EXAMPLE 10 1,3-Dihydro-8-chloro-7-methyl-2H-imidazo[4,5-b]quinolin-2-one##STR28##

This compound was prepared analogous to Example 2 from5-[(2-chloro-3-methyl-6-nitrophenyl)methyl]-2,4-imidazolidinedione. Thetitle product is obtained as a hydrate (55%), m.p.>360° C.

Anal. Calcd. for C₁₁ H₈ ClN₃ O.0.2H₂ O: C, 55.69; H, 3.57; N, 17.71; H₂O, 1.52. Found: C, 54.61; H, 3.47; N, 17.11; H₂ O, 1.43.

NMR (DMSO-d₆): 2.50 (3, s); 7.57 (2, AB quartet, 8 Hz); 7.69 (1, s);11.10 (1, bs); 11.60 (1, bs).

EXAMPLE 117-Chloro-1,3-dihydro-6,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one##STR29##

This compound was prepared analogous to Example 8 from5-[(2,4-dimethyl-3-chloro-6-nitro)methyl]-2,4-imidazolidinedione (70%),m.p.>300° C.

Anal. Calcd. for C₁₂ H₁₀ ClN₃ O: C, 58.19; H, 4.07; N, 16.97. Found: C,57.92; H, 4.10; N, 17.03.

NMR (CF₃ CO₂ H): 2.73 (3, s); 2.93 (3, s); 7.84 (1, s); 8.90 (1, s).

EXAMPLE 12 7-Methoxy-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one##STR30##

A solution of5-[(2-nitro-5-methoxyphenyl)methylene]-2,4-imidazolidinedione (4.5 g, 17mmol) in dimethylformamide (120 mL) was hydrogenated over 10% palladiumon charcoal (0.45 g) at 60 psi. After 42 hours the mixture was filteredthrough infusorial earth and the solvent evaporated to leave a brownsolid. A mixture of this material and methanol (150 mL) was heated toreflux and iodine (3.65 g, 14 mmol) introduced portionwise over 15minutes. The reaction mixture was refluxed 45 minutes, cooled andconcentrated to 20 mL before adding a solution of sodium thiosulfte (10g) and sodium carbonate (10 g) in water (200 mL). The precipitate wasfiltered off, suspended in hot (80° C.) water (200 mL) and filtered.Recrystallization from aqueous dimethylformamide afforded7-methoxy-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (1.61 g, 43%),m.p.>360° C.

Anal. Calcd. for C₁₁ H₉ N₃ O₂ : C, 61.39; H, 4.22; N, 19.53. Found: C,61.21; H, 4.27; N, 19.53.

NMR (DMSO-d₆): 3.79 (3, s); 7.10 (1, dd, 3 Hz, 9 Hz); 7.28 (1, d, 3 Hz);7.48 (1, s); 7.65 (1, d, 9 Hz); 10.90 (1, bs); 11.32 (1, bs).

EXAMPLE 13 1,3-Dihydro-6,7-dimethoxy-2H-imidazo[4,5-b]quinolin-2-one##STR31##

This compound was prepared analogous to Example 7(b) from5-[(4,5-dimethoxy-2-nitrophenyl)methyl]-2,4-imidazolidinedione. Thetitle product is obtained as a white powder (34%), m.p.>320° C.

Anal. Calcd. for C₁₂ H₁₁ N₃ O₃ : C, 58.77; H, 4.52; N, 17.13. Found: C,58.38; H, 4.55; N, 17.09.

NMR (DMSO-d₆): 3.88 (6, s); 7.20 (1, s); 7.30 (1, s); 7.49 (1, s); 10.50to 11.50 (2, bs).

EXAMPLE 147-Bromo-1,3-dihydro-6,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one##STR32##

This compound was prepared analogous to Example 5 from5-[(2,4-dimethyl-3-bromo-6-nitro)methyl]-2,4-imidazolidinedione (74%),m.p.>300° C.

Anal. Calcd. for C₁₂ H₁₀ BrN₃ O: C, 49.34; H, 3.45; N, 14.38. Found: C,49.27; H, 3.50; N, 14.42.

NMR (CF₃ CO₂ H): 2.76 (3, s); 2.98 (3, s); 7.81 (1, s); 8.90 (1, s).

EXAMPLE 15

Additional Formula I compounds are prepared by reducing theappropriately substituted hydantoin of Formula II (obtained according toMethods A or B or C) in a manner analogous to the above examples.

    ______________________________________                                         ##STR33##                                                                    Example No.  R.sub.1       R.sub.2 R.sub.3                                    ______________________________________                                        15-1         5-CH.sub.3    H       H                                          15-2         5-CH.sub.3 O  H       H                                          15-3         5-Cl          H       H                                          15-4         7- -n-C.sub.4 H.sub.7 O                                                                     H       H                                          15-5         7-(CH.sub.3).sub.3 CO                                                                       H       H                                          15-6         7-(CH.sub.3).sub.2 CHO                                                                      H       H                                          15-7         7-C.sub.2 H.sub.5 O                                                                         H       H                                          15-8         5-CH.sub.3    7-CH.sub.3                                                                            H                                          15-9         5-CH.sub.3    8-CH.sub.3                                                                            H                                          ______________________________________                                    

EXAMPLE 16 Method A--Preparation of hydantoin intermediates of FormulaII wherein a and b are hydrogen by adaptation of the method of Conners,et al. supra. ##STR34## (a)5-[(2,3-dimethyl-6-nitrophenyl)methyl]-2,4imidazolidinedione (R₁ =H, R₂=R₃ =CH₃)

Step 1. Diethyl2-(acetylamino)-2-[(2,3-dimethyl-6-nitrophenyl)methyl]propanedioate.Sodium (3.38 g, 0.15 g atom) was dissolved in ethanol (600 mL) anddiethyl acetamidomalonate (29.04 g, 0.13 mole) added in one portion. Themixture was stirred for 10 minutes and a solution of2,3-dimethyl-6-nitrobenzyl chloride (26.70 g, 0.13 mol) in ethanol (30mL) added. The mixture was heated under reflux for 4 hours, stirred atroom temperature for 12 hours and then concentrated in vacuo. Theresidue was diluted with water and extracted with dichloromethane. Thecombined extracts were dried over sodium sulfate and the solventevaporated to leave a viscous oil which was filtered through a plug ofsilica gel 6"×11/2" using diethyl ether as eluent. The residue, afterremoval of the solvent was dissolved in dichloromethane and diluted withhexane to givediethyl-2-(acetylamino)-2-[(2,3-dimethyl-6-nitrophenyl)methyl]propanedioate(28.90 g, 56%). A second crop (2.3 g, 4%) was subsequently collected,m.p. 112°-113° C. Spectral data were in accord with the assignedstructure.

Anal. Calcd. for C₁₈ H₂₄ N₂ O₇ : C, 56.84; H, 6.36; N, 7.36. Found: C,56.79; H, 6.32; N, 7.30.

Step 2. DL-2,3-dimethyl-6-nitrophenylalanine hydrochloride. A mixture ofdiethyl2-(acetylamino)-2-[(2,3-dimethyl-6-nitrophenyl)methyl]propanedioate(28.75 g, 75 mmol), concentrated hydrochloric acid solution (150 mL) andwater (150 mL) was heated under reflux. After 19 hours, the solvent wasevaporated and the solid residue dissolved in methanol (about 150 mL).Addition of the diethyl ether (about 800 mL) precipitatedDL-2,3-dimethyl-6-nitrophenylalanine hydrochloride hydrate (16.50 g,79%), m.p. 215°-217° C. (dec) which exhibited spectral data in accordwith the designated structure.

Anal. Calcd. for C₁₁ H₁₄ N₂ O₄.HCl.0.25H₂ O: C, 47.32, H, 5.60; N,10.03; Cl, 12.70; H₂ O, 1.61. Found: C, 46.98; H, 5.62; N, 10.28; Cl,12.45; H₂ O, 1.52.

Step 3. DL-N-(Aminocarbonyl)-2,3-dimethyl-6-nitrophenylalanine Potassiumcyanate (17.5 g, 0.21 mol) was added to stirred solution ofDL-2,3-dimethyl-6-nitrophenylalanine hydrochloride (15 g, 0.05 mol) inwater (125 mL). The mixture was heated on a steam bath for 30 minutes,cooled and acidified with 2N hydrochloric acid solution. The precipitatewas filtered off, washed with water and dried in air to giveDL-N-(aminocarbonyl)-2,3-dimethyl-6-nitrophenylalanine as a hydrate(16.0 g, 100%), m.p. 223°-224° C. (dec). Spectral data were in accordwith the assigned structure.

Anal. Calcd. for C₁₂ H₁₅ N₃ O₅ 0.2H₂ O: C, 50.60; H, 5.45; N, 14.75; H₂O, 1.27. Found: C, 50.45; H, 5.31; N, 15.15; H₂ O, 1.28.

Step 4. 5-[(2,3-Dimethyl-6-nitrophenyl)methyl]-2,4-imidazolidinedione. Amixture of DL-N-(aminocarbonyl)-2,3-dimethyl-6-nitrophenylalaninehydrate (15.5 g, 50 mmol) and 10% hydrogen chloride in ethanol (200 mL)was heated at reflux for 19 hours. The reaction mixture was diluted withmethanol (100 mL) and filtered to give5-[(2,3-dimethyl-6-nitrophenyl)methyl]-2,4-imidazolidinedione (3.35 g).Concentration of the mother liquors afforded a solid which was suspendedin methanol and filtered to afford a second crop (3.76 g). Total yield(7.20 g, 50%). Crystallizing a sample from methanol afforded the titleintermediate analytically pure as hydrated material, m.p. 172°-174° C.,which exhibited spectral data in accord with the assigned structure.

Anal. Calcd. for C₁₂ H₁₃ N₃ O₄ 0.2H₂ O: C, 54.01; H, 5.06; N, 15.75; H₂O, 1.35. Found: C, 53.90; H, 4.93; N, 15.84; H₂ O, 1.32.

(b) 5-[(2-Chloro-6-nitrophenyl)methyl]-2,4-imidazolidinedione (R₁ =R₂=H, R₃ =Cl)

A mixture of DL-N-(aminocarbonyl)-2-chloro-6-nitrophenylalanine (6.15 g,21 mmol) prepared from 2-chloro-6-nitrobenzyl chloride according tosteps 1, 2 and 3 above, concentrated hydrochloric acid (70 mL) and water(70 mL) was heated on a steam bath. After 45 minutes, the mixture wascooled, filtered and the solid washed with water and dried in air togive 5-[(2-chloro-6-nitrophenyl)methyl]-2,4imidazolidinedione (4.90 g,85%), which was used without further purification. An analytical samplewas prepared by dissolving a sample of the crude material (0.6 g) inboiling ethanol (30 mL) and adding ether to precipitate pure material(0.48 g). m.p. 210°-212° C. (dec). Spectral data were in accord with theassigned structure.

Anal. Calcd. for C₁₀ H₈ ClN₃ O₄ : C, 44.54; H, 2.99; N, 15.58; Cl,13.15. Found: C, 44.57; H, 3.07; N, 15.42; Cl, 13.08.

(c) 5-[(5-Fluoro-2-nitrophenyl)methyl]-2-imidazolidinedione (R₁ =R₃ =H,R₂ =F)

Prepared from 5-fluoro-2-nitrobenzyl chloride according to the procedureof Method A, m.p. 186°-188° C. from methanol.

Anal. Calcd. for C₁₀ H₈ FN₃ O₄ : C, 47.44; H, 3.19; N, 16.60. Found: C,47.14; H, 3.20; N, 16.90.

(d) 5-[(2-methyl-6-nitrophenyl)methyl]-2,4-imidazolidinedione (R₁ =R₂=H, R₃ =CH₃)

Prepared from 2-methyl-6-nitrobenzyl chloride according to the procedureof Method A, m.p. 225°-226° C. (dec) from ethanol.

Anal. Calcd. for C₁₁ H₁₁ N₃ O₄ : C, 53.01; H, 4.45; N, 16.86. Found: C,53.14; H, 4.56; N, 16.80.

(e) 5-[(5-Methyl-2-nitrophenyl)methyl]-2,4-imidazolidinedione (R₁ =R₃=H, R₂ =CH₃)

Prepared from 5-methyl-2-nitrobenzyl chloride according to the procedureof Method A, m.p. 222°-225° C. (dec) from ethanol.

Anal. Calcd. for C₁₁ H₁₁ N₃ O₄ : C, 53.01; H, 4.45; N, 16.86. Found: Cd,52.69; H, 4.54; N, 16.78.

(f) 5-[(5-Chloro-2-nitrophenyl)methyl]-2,4-imidazolidinedione (R₁ =R₃=H, R₂ =Cl)

Prepared from 5-chloro-2-nitrobenzyl chloride according to the procedureof Method A, m.p. 184°-186° C. from aqueous HCl.

Anal. Calcd. for C₁₀ H₈ ClN₃ O₄ : C, 44.54; H, 2.99; N, 15.58; Cl,13.15. Found: C, 44.35; H, 3.01; N, 15.25; Cl, 13.66.

(g) 5-[(4,5-Dimethyl-2-nitrophenyl)methyl]-2,4-imidazolidinedione (R₃=H, R₁ =R₂ =CH₃)

Prepared from 4,5-dimethyl-2-nitrobenzyl chloride according to theprocedure of Method A, m.p. 248°-149° C. (dec) from ethanol.

Anal. Calcd. for C₁₂ H₁₃ N₃ O₄ : C, 54.75; H, 4.98; N, 15.96. Found: C,54.48; H, 5.11; N, 15.64.

EXAMPLE 17 METHOD B. Preparation of hydantoin intermediates of FormulaII wherein a and b are hydrogen ##STR35## (a)5-[(5-Chloro-4-methyl-2-nitrophyenyl)methyl]-2,4-imidazolidinedione (R₁=CH₃, R₂ =Cl, R₃ =H)

Step 1. Ethyl4-[(5-chloro-4-methyl-2-nitrophenyl)methyl]-2,5-dioxoimidazolidine-4-carboxylate.Ethyl 2,5-dioxoimidazolidine-4-carboxylate, sodium salt (15.50 g, 80mmol) obtained according to Garner, et al., J. Org. Chem., 20, 2003-2005(1964) was added to a solution of 5-chloro-2-nitro benzyl chloride(17.57 g, 80 mmol) in ethanol (250 mL) and the mixture refluxed under anatmosphere of argon for 16 hours. The solvent was evaporated, theresidue diluted with water and extracted with dichloromethane. Thecombined extracts were dried over sodium sulfate and concentrated invacuo to afford a solid which was dissolved in dichloromethane. Additionof hexane precipitated ethyl4-[(5-chloro-4-methyl-2-nitrophenyl)methyl]-2,5-dioxoimidazolidine-4-carboxylate(12.35 g, 43%), m.p. 176°-178° C. which exhibited spectral data inaccord with assigned structure.

Anal. Calcd. for C₁₄ H₁₄ ClN₃ O₆ : C, 47.27; H, 3.97; N, 11.81; Cl,9.97. Found: C, 46.95; H, 3.90; N, 11.79; Cl, 10.38.

Step 2.5-[(5-Chloro-4-methyl-2-nitrophenyl)methyl]-2,4-imidazolidinedione. Amixture of ethyl4-[(5-chloro-4-methyl-2-nitrophenyl)methyl]-2,5-dioxoimidazolidine4-carboxylate (11.85 g, 33 mmol) concentrated hydrochloric acid (175 mL)and water (175 mL) was heated under reflux for 2 hours. After cooling,the precipitate was filtered off, washed with water and dried in vacuoat 78° C. to afford5-[(5-chloro-4-methyl-2-nitrophenyl)methyl]-2,4-imidazolidinedione (8.76g, 95%), m.p. 211°-214° C. which displayed spectral data in accord withassigned structure.

Anal. Calcd. for C₁₁ H₁₀ ClN₃ O₄ : C, 46.58; H, 3.55; N, 14.81; Cl,12.50. Found: C, 46.68; H, 3.47; N, 14.88; Cl, 12.72.

(b) 5-[(2-Methoxy-6-nitrophenyl)methyl]-2,4-imidazolidinedione (R₁ =R₂=H, R₃ =CH₃ O)

Prepared from 2-methoxy-6-nitrobenzyl bromide according to the procedureof Method B, m.p. 193°-194° C.

Anal. Calcd. for C₁₁ H₁₁ N₃ O₅ : C, 49.82; H, 4.18; N, 15.84. Found: C,49.78; H, 4.15; N, 15.91.

(c) 5-[(6-Chloro-5-methyl-2-nitrophenyl)methyl]-2,4-imidazolidinedione(R₁ =H, R₂ =CH₃, R₃ =Cl)

Prepared from 2-chloro-3-methyl-6-nitrobenzyl bromide according to theprocedure of Method B, m.p. 203°-205° C.

Anal. Calcd. for C₁₁ H₁₀ ClN₃ O₄ : C, 46.58; H, 3.55; N, 14.81. Found:C, 46.31; H, 3.53; N, 14.80.

(d) 5-[2,4-Dimethyl-3-chloro-6-nitro)methyl]-2,4-imidazolidinedione (R₁=R₃ =CH₃, R₂ =Cl).

Prepared from 2,4-dimethyl-3-chloro-6-nitrobenzyl bromide according tothe procedure of Method B, m.p. 200°-201.5° C.

(e) 5-[(4,5-Dimethoxy-2-nitrophenyl)methyl]-2,4-imidazolidinedione (R₁=R₂ =CH₃ O, R₃ =H).

Prepared from 4,5-dimethoxy-2-nitrobenzyl bromide according to theprocedure of Method B, m.p. 207°-208° C.

Anal. Calcd. for C₁₂ H₁₃ N₃ O₆ : C, 48.82; H, 4.44; N, 14.23. Found: C,48.72; H, 4.40; N, 14.31.

(f) 5-[(2,4-Dimethyl-4-bromo-6-nitro)methyl]-2,4-imidazolidinedione (R₁=R₃ =CH₃, R₂ =Br).

Prepared from 2,4-dimethyl-3-chloro-6-nitrobenzyl chloride according tothe procedure of Method B, m.p. 199°-201° C.

EXAMPLE 18 METHOD C.--Preparation of hydantoin intermediates of FormulaII wherein a and b together form a covalent bond by adaptation of themethod of Billek, supra ##STR36## (a)5-[(2-Nitro-5-methoxyphenyl)methylene]-2,4-imidazolidinedione (R₁ =R₃=H, R₂ =CH₃ O).

A mixture of 5-methoxy-2-nitrobenzaldehyde (10.0 g, 55 mmol),imidazolidine-2,4-dione (5.52 g, 55 mmol), fused sodium acetate (4.53 g,55 mmol) and acetic anhydride (75 mL) was heated under reflux for 1hour. The mixture was cooled and water (30 mL) added producing anexothermic reaction. The mixture was additionally diluted with water(270 mL) added portionwise over 15 minutes and then extracted withdichloromethane (2×100 mL). Combined extracts were dried over sodiumsulfate and concentrated to afford the acylated5-[(2-nitro-5-methoxyphenyl)methylene]-2,4-imidazolidinedione as an oilwhich is used as follows without further purification. The oil wasdissolved in methanol (150 mL) and 4N sodium hydroxide solution (150 mL)added. The reaction mixture was stirred for 1 hour, acidified to pH=2with 2N HCl and a tan precipitate filtered off, washed with water anddried in air. This material suspended in methanol and filtered gave5-[(2-nitro-5-methoxyphenyl)methylene]-2,4-imidazolidinedione (8.0 g,55%), m.p. 294°-295° C. (dec.) which exhibited spectral data in accordwith the assigned structure.

Anal. Calcd. for C₁₁ H₉ N₃ O₅ : C, 50.20; H, 3.45; N, 15.96. Found: C,49.94; H, 3.51; N, 15.64.

EXAMPLE 19 Preparation of Formula IIA compounds wherein a and b arehydrogen

General Procedure. A solution of a Formula II nitro-hydantoin (8 mmol)in dimethylformamide (60 mL) is hydrogenated over 10%palladium-on-charcoal (0.4 g) at 60 p.s.i. After hydrogen uptake ceased,the mixture is filtered through infusorial earth and the solventevaporated under reduced pressure. Residual material consists of theFormula IIA amino-hydantoin which can be used to provide Formula IIBcompounds without further purification. If desired, residual materialcan be further purified by conventional methods such as trituration orcrystallization from an appropriate solvent.

The compounds tabulated below can be prepared according to thisprocedure from the corresponding Formula II nitro-hydantoin.

                  TABLE III                                                       ______________________________________                                         ##STR37##                                                                    IIA (a = b = H)                                                               Example    R.sub.1     R.sub.2    R.sub.3                                     ______________________________________                                        19-1       H           H          6-Cl                                        19-2       H           5-F        H                                           19-3       H           H          6-CH.sub.3                                  Triturated from diethyl ether, 90% yield, m.p.                                308-310° C. (dec). NMR spectra indicates partial                       dimethylformamide solvate.                                                    Anal. Calcd. for C.sub.11 H.sub.13 N.sub.3 O.sub.2. 0.2 C.sub.3 H.sub.7       NO: C, 59.58;                                                                 H, 6.21; N, 19.17. Found: C, 59.30; H, 6.17; N, 18.75.                        19-4       H           5-CH.sub.3 H                                           19-5       H           5-Cl       H                                           19-6       4-CH.sub.3  5-CH.sub.3 H                                           19-7       H           5-CH.sub.3 6-CH.sub.3                                  19-8       4-CH.sub.3  5-Cl       H                                           19-9       H           H          6-CH.sub.3 O                                 19-10     H           5-CH.sub.3 6-Cl                                         19-11     4-CH.sub.3  5-Cl       6-CH.sub.3                                   19-12     H           5-CH.sub.3 O                                                                             H                                            19-13     HCH.sub.3 O 5-CH.sub.3 O                                                                             H                                            19-14     4-CH.sub.3  5-Br       6-CH.sub.3                                  ______________________________________                                    

EXAMPLE 20 Preparation of1,3,9,9a-Tetrahydro-2H-imidazo[4,5-b]quinolin-2-one Intermediates ofFormula IIB

General Procedure. A mixture of a Formula IIA amino-hydantoin wherein aand b are hydrogen (16 mmol) and p-toluenesulfonic acid monohydrate(0.25 g) in methanol (180 mL) is heated to reflux under an inertatmosphere (e.g. argon) for a period of 1.25 hours. Removal of thesolvent under reduced pressure affords the Formula IIBtetrahydroquinoline. Purification is carried out by conventional methodssuch as crystallization or trituration of the residual material fromsolvents such as methanol, ether, and the like. If desired, acidaddition salts of the Formula IIB tetrahydroquinoline can be prepared byacidifying the residual material in an appropriate solvent.

The compounds tabulated below can be prepared according to thisprocedure from the corresponding Formula IIA aminohydantoins wherein aand b are hydrogen.

                  TABLE IV                                                        ______________________________________                                         ##STR38##                    (IIB)                                           Example  R.sub.1      R.sub.2  R.sub.3                                        ______________________________________                                        20-1     H            H        8-Cl                                           20-2     H            7-F      H                                              20-3     H            H        8-CH.sub.3                                     Acidification of the residual material with methanolic                        hydrogen chloride and precipitation with diethyl ether                        provided a 62% yield of hydrated 8-methyl-1,3,9,9a-                           tetrahydro-2Himidazo[4,5-b]quinolin-2-one hydro-                              chloride, m.p. 220-225° C. (dec).                                      Anal. Calcd. for C.sub.11 H.sub.11 N.sub.3 O.HCl.0.55 H.sub.2 O: C,           53.36;                                                                        H, 5.33; N, 16.97; H.sub.2 O, 4.00. Found: C, 53.03;                          H, 5.44; N, 16.74; H.sub.2 O, 3.49.                                           NMR (DMSO-d.sub.6): 2.29 (3,s); 2.78 (1,t, J = 15 Hz),                        3.30 (1,dd, J = 15 Hz, J' = 8 Hz); 4.92 (1,dd, J = 15 Hz,                     J' = 8 Hz); 7.15 to 7.60 (3,m); 9.20 (1,bs); 9.80 (2,bs).                     20-4     H            7-CH.sub.3                                                                             H                                              20-5     H            7-Cl     H                                              20-6     6-CH.sub.3   7-CH.sub.3                                                                             H                                              20-7     H            7-CH.sub.3                                                                             8-CH.sub.3                                     20-8     6-CH.sub.3   7-Cl     H                                              20-9     H            H        8-CH.sub.3 O                                    20-10   H            7-CH.sub.3                                                                             8-Cl                                            20-11   6-CH.sub.3   7-Cl     8-CH.sub.3                                      20-12   H            7-CH.sub.3 O                                                                           H                                               20-13   6-CH.sub.3 O 7-CH.sub.3 O                                                                           H                                               20-14   6-CH.sub.3   7-Br     8-CH.sub.3                                     ______________________________________                                    

EXAMPLE 21 Preparation of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-onesof Formula I from 1,3,9,9a-tetrahydro2H-imidazo[4,5-b]quinolin-2-oneIntermediates of Formula IIB

General Procedure. Iodine (0.63 g, 2.5 mmol) is added portionwise over30 seconds to a suspension of a Formula IIB1,3,9,9a-tetrahydro-2H-imidazo[4,5-b]quinolin-2-one (2.5 mmol) inrefluxing methanol (20 mL). The mixture is heated under reflux for 15minutes, cooled, concentrated to approximately (5 mL) and treated with asolution of sodium thiosulfate (1 g) and sodium carbonate (1 g) in water(20 mL) with vigorous stirring. The insoluble product is collected,washed with water and dried. Other conventional purification methods canbe employed such as concentrating the reaction mixture under reducedpressure and triturating the residual material with an appropriatesolvent such as water, lower alkanols, etc.

If desired, acid addition salts of the Formula I products can beprepared by acidifying the residual material in an appropriate solvent.For instance, treating8-methyl-1,3,9,9a-tetrahydro-2H-imidazo[4,5-b]quinolin-2-one with iodineas above and dissolving the insoluble product in a 10% methanolichydrogen chloride solution followed by addition of diethyl etherprovided a 72% yield of8-methyl-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one hydrochloride, m.p.360°-363° C.

Anal. Calcd. for C₁₁ H₉ N₃ O.HCl: C, 56.06; H, 4.28; N, 17.83. Found: C,55.95; H, 4.24; N, 17.65.

NMR (DMSO-d₆): 2.63 (3, s); 7.33 (1, d, J=8 Hz); 7.50 (1, t, J=Hz); 7.76(1, s); 7.82 (1, d), J=8 Hz); 11.60 (1, s); 11.90 (2, bs).

FURTHER DETAILED DESCRIPTION OF THE INVENTION

Formula XII below redefines scope of the invention to include compoundsof Formula I and additional compounds simlar thereto. In particular,Formula XII embodies compounds wherein the "imidazo-2-one heterocycle"fragment of Formula I is substituted with lower alkyl (preferablymethyl) at the 1-position in addition to hydrogen. Further, the R₁substituent has been expanded to include trifluoromethyl. Thus thepresent invention comprehends a compound of Formula XII ##STR39##wherein R₁ is halogen, lower alkyl, lower alkoxy, trifluoromethyl;

R₂ is hydrogen, halogen, lower alkyl, lower alkoxy;

R₃ is hydrogen, halogen, lower alkyl, lower alkoxy;

R₄ is hydrogen, lower alkyl

or a pharmaceutically acceptable salt thereof.

It is to be understood that previously mentioned references to Formula Iare to be read herein as including Formula XII compounds.

A preferred group of compounds are those of Formula XII wherein R₁, R₂and R₃ are attached at the 6, 7, and 8 position, respectively, and amost preferred group are those wherein R₁, R₂ and R₃ are similarlyattached and R₄ is hydrogen.

The compounds of Formula XII are obtained according to the process setforth for Formula I compounds. Thus, the compounds characterized byFormula XII ##STR40## wherein R₁ is halogen, lower alkyl, lower alkoxy,trifluoromethyl; R₂ is hydrogen, halogen, lower alkyl, lower alkoxy; R₃is hydrogen, halogen, lower alkyl, lower alkoxy; and R₄ is hydrogen,lower alkyl, are obtained by a process comprising

(a) reducing a substituted hydantoin of Formula XIII ##STR41## wherein aand b are hydrogen or together are a covalent bond, R₁, R₂, R₃ and R₄are defined as above; and

(b) treating the reduced material with an oxidant such as iodine whenrequired.

The foregoing process is analogous to the previously described processfor reducing a Formula II hydantoin and treating reduced material withan oxidant such as iodine when required. Accordingly, reduction ofFormula XIII hydantoin intermediates is carried out by conventionalchemical or catalytic methods. For instance, the Formula XIII hydantoinscan be chemically reduced by treatment with hydrogen iodide and redphosphorus according to the method of Kozak, et al., supra. Catalytichydrogenation is particularly preferred and accomplished with atransition metal catalyst, preferably palladium-on-carbon, in anappropriate reaction inert solvent such as dimethylformamide. Reductionis carried out at room temperature and when hydrogen uptake isessentially complete, the reaction mixture is warmed and filtered oroptionally heated to about 100° C., for a 1 to 4 hour period beforefiltering. In some instances, residual material obtained byconcentrating the filtrate predominantly consists of the desired FormulaXII product produced by facile cyclization and aratomization to thefused quinoline ring system. In other instances, the residual materialpredominantly consists of the uncyclized Formula XIIIA amino hydantoin(wherein a and b, R₁, R₂, R₃, R₄ are as defined above) resulting fromreduction of the Formula XIII nitro hydantoin or the4,5-dihydroquinoline intermediate of Formula XIIIB (wherein R₁, R₂, R₃,and R₄ are defined as above). In other instances, the residual materialpredominantly consists of a mixture of Formula XIIIA, XIIIBintermediates together with the desired Formula XII product. Withoutbeing bound by theory, the transformation of a Formula XIIInitro-hydantoin to the Formula XII product is thought to involvereduction of the nitro group and olefenic double bond to thecorresponding Formula XIIIA amine (wherein a and b are hydrogen). Ringcyclization follows or occurs simultaneously to the Formula XII productor the 1,3,9,9a-tetrahydroquinoline intermediate of Formula XIIIB whichis aromatized by dehydrogenation. ##STR42## In those cases where thereaction is incomplete, the residual material is treated with an oxidantsuch as iodine in an alkanol solvent such as methanol ordimethylformamide and the like at reflux temperature. Under theseconditions, cyclization of Formula XIIIA amines to the Formula XIIproducts or the Formula XIIIB tetrahydroquinoline intermediates withoxidation of the latter to the desired1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones of Formula XII is effected.The Formula XIIIA and XIIIB compounds are considered part of the instantinvention. When iodine is employed, the Formula XII product is isolatedin base form by sequentially treating the reaction mixture with aqueoussodium thiosulfate and alkali metal carbonate such as sodium carbonate.Conversion of the base form to pharmaceutically acceptable acid additionsalts is carried out by conventional means.

An alternate process for preparing Formula XII compounds comprises

(a) alkylating a thio compound of Formula XIV ##STR43## wherein R₁, R₂,R₃ and R₄ are as defined above with R₅ X wherein R₅ is lower alkyl and Xrepresents a leaving group such as mesylate, tosylate, phosphate,sulfate and halogen, preferably chlorine or bromine to provide analkylated thio compound of Formula XV ##STR44##

(b) and then hydrolyzing the Formula XV compound, preferably under acidconditions, to the Formula XII compound.

With reference to preparation of Formula XIII hydantoins wherein a and brepresent a covalent bond, the procedure described by Billek, supra.,can be used. Additionally, Formula XIII hydantoins can be obtained byreaction of a hydantoin-5-phosphonate of Formula XVI wherein R₄ ishydrogen or lower alkyl with a 2-nitrobenzaldehyde of Formula IX'(wherein R₁, R₂ and R₃ are as defined for Formula XII) illustrated inthe following reaction scheme. ##STR45## The reaction is convenientlycarried out at room temperature by adding the phosphonate (XVI) to amolar equivalent of sodium dissolved in an alkanol solvent such asethanol followed by addition of the benzaldehyde (IX' wherein R₁, R₂, R₃are as defined for XIII). A relatively short period of time is requiredto complete the reaction (e.g. 0.5 to 2 hours) and the hydantoin (XIIIwherein a+b=covalent bond) is isolated by concentrating the reactionmixture and washing the residue with water. The hydantoin derivatives(XIII wherein a+b=covalent bond) thus obtained frequently consist of amixture of geometrical isomers wherein the predominate isomer has thevinyl proton (where present) resonating at lower field in the NMRspectrum. In the instant process for preparing Formula XII compoundsfrom hydantoins (XIII wherein a+b=covalent bond), it is immaterial as towhich isomer is used since the double bond is reduced.

With reference to preparation of Formula XIV1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-thiones, the following series ofreactions are used. ##STR46## In step 1 of Method E, the aldehyde (XVIIwherein R₁, R₂ and R₃ are as defined for XIV) is condensed with the R₄-2-thiohydantoin (XVIII wherein R₄ is hydrogen or lower alkyl) inaqueous ethanol and morpholine or piperidine at steam bath temperature.In Step 2, the amino function of (XIX) is deprotected by dissolving thematerial in neat trifluoro acetic acid in the presence of anisole togive the aniline intermediate (XX). Cyclization of (XIX) was effected byexposure to pyridinium tosylate in diphenyl ether at 180° C. to furnishthione (XIV).

A variation of Method E involves substituting an appropriate hydantoinfor the R₄ -thiohydantoin in Step 1 and condensing with phosphonate(XVI). Subsequent hydrolysis (Step 2) and cyclization (step 3) affordsthe instant compounds of Formula XII. For instance, the following seriesof reactions provides1,3-dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one. ##STR47##

EXAMPLE 22 7-Bromo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one ##STR48##

Step 1. N-[2[(2,4-Dioxo-5-imidazolidinyl)methyl]phenyl]acetamide hydrate

N-[2-[(2,4-Dioxoimidazolidin-5-ylidene)methyl]phenyl]acetamide obtainedby condensing 2-acetamidobenzaldehyde with phosphonate (XVI) (47 g, 0.19mole) in dimethylformamide (400 mL) was hydrogenated at 50° p.s.i. over10% palladium on charcoal (3 g). After 7 hours, the mixture was filteredthrough kieselguhr, the solvent evaporated and the residue trituratedwith water (100 mL). After standing overnight at 5° C., the solid wascollected by filtration, washed with cold water and dried in vacuo at80° C. to give N-[2-[(2,4-dioxo-5-imidazolidinyl)methyl]phenyl]acetamide(47.15 g, 100%) which was used in Step 2 without further purification. Ahydrated analytical sample purified by crystallization from aqueousethanol had m.p. 200°-202° C.

Anal. Calcd. for C₁₂ H₁₃ N₃ O₃.0.09H₂ O: C, 57.92; N, 5.34; N, 16.89; H₂O, 0.65. Found: C, 57.59; H, 5.38; N, 16.91; H₂ O, 0.63.

Step 2. N-[4-Bromo-[(2,4-dioxo-5-imidazolidinyl)methyl]phenyl]acetamide

Bromine (23.26 g, 0.146 mole) in acetic acid (10 mL) was added dropwiseto a stirred solution ofN-[2-[(2,4-dioxo-5-imidazolidinyl)methyl]phenyl]acetamide (34.24 g,0.139 mole) and sodium acetate (12.54 g, 0.153 mole) in acetic acid (300mL) maintained at 65° C. The mixture was stirred at 65° C. for 18 hoursduring which time a heavy precipitate developed. The mixture was cooled,diluted with water (1 L) and sodium sulfite solution (added untilbromine color disappears) and filtered to afford a white solid (about 17g). The filtrate was concentrated in vacuo to afford a white solid whichwas triturated with water (100 mL) and filtered to give an additional 17g of material. The combined solids were washed with diethyl ether anddried in vacuo at 50° C. to giveN-[4-bromo-2-[2,4-dioxo-5-imidazolidinyl)methyl]phenyl]acetamide (30.78g, 94%) which was used in Step 3 without further purification. Ananalytical sample prepared by crystallization from ethanol had m.p.216°-220° C.

Anal. Calcd. for C₁₂ H₁₂ BrN₃ O₃ : C, 44.19; H, 3.71; N, 12.88. Found:C, 44.30; H, 3.79; N, 12.84.

Step 3. 5-[(2-Amino-5-bromophenyl)methyl]-2,4-imidazolidinedione

A mixture ofN-[4-bromo-2-[(2,4-dioxo-5-imidazolidinyl)methyl]phenyl]acetamide (30.78g, 94 mmol), ethanol (375 mL) and 10% hydrochloric acid solution (190mL) was refluxed for 2.5 hours. The mixture was cooled to 5° C. and thesolid (18.58 g) filtered off. The filtrate was concentrated in vacuo,neutralized with sodium bicarbonate solution, the precipitate filteredoff and combined with ethanol (15 mL) and 10% hydrochloric acid solution(10 mL). After refluxing for 1.5 hours, the mixture was cooled andfiltered to give an additional 1.95 g of material which was combinedwith the previously isolated material to give5-[(2-amino-5-bromophenyl)methyl]-2,4-imidazolidinedione (20.53 g, 77%),m.p. >310° C.

Anal. Calcd. for C₁₀ H₁₀ BrN₃ O₂ : C, 42.28; H, 3.55; N, 14.79. Found:C, 42.10; H, 3.57; N, 14.70.

Step 4. 7-Bromo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one. Iodine(8.93 g, 0.35 mmole) was added in one portion to a solution of5-[(2-amino-5-bromophenyl)methyl]-2,4-imidazolidinedione (10.00 g, 35mmol) in dimethylformamide (150 mL) maintained at reflux. After 5minutes, the mixture was cooled to room temperature, diluted with water(300 mL) and sodium sulfite solution added until colorless. Sodiumcarbonate (10%) solution was then added to pH=9 and the solid wasfiltered off, washed with water and ethanol and dried in vacuo at 78° C.overnight to give 7-bromo-1,3-dihydro-2Himidazo[4,5-b]quinolin-2-one(8.45 g, 90%), m.p. >310° C.

Anal. Calcd. for C₁₀ H₆ BrN₃ O: C, 45.49; H, 2.30; N, 15.92. Found: C,45.69; H, 2.42; N, 15.85.

NMR (DMSO-d₆): delta 7.61 (1H, dd, J=9 Hz, J'=2 Hz, aromatic H, 7.62(1H, s); 7.71 (1H, d, J=9 Hz), 8.15 (1H, d, J=2 Hz).

EXAMPLE 231,3-Dihydro-7-(1-methylethoxy)-2H-imidazo[4,5-b]quinolin-2-one ##STR49##

This compound (previously disclosed as Example 15-6) was preparedanalogous to Example 12 from5-[[5-(1-methylethoxy)-2-nitro]methylene]-2,4-imidazolidinedione (39%),m.p. >320° C.

Anal. Calcd. for C₁₃ H₁₃ N₃ O₂ : C, 64.19; H, 5.39; N, 17.27. Found: C,64.31; H, 5.40; N, 7.11.

NMR (DMSO-d₆): delta 1.34 (6H, d, J=5.5 Hz, ##STR50## 4.68 (1H, m, OCH,7.16 (1H, d, J=9 Hz, aromatic ortho to --O--), 7.35 (1H, s), 7.59 (1H,s, aromatic H0 ortho to NCO), 7.76 (1H, d, J=9 Hz, aromatic H0 ortho to--O--), 11.04 (1H, bs, NH), 11.45 (1H, bs, NH).

EXAMPLE 24 1,3-Dihydro-6,7,8-trimethoxy-2H-imidazo[4,5-b]quinolin-2-one##STR51##

This compound is prepared analogous to Example 12 from5-[4,5,6-trimethoxy-2-nitrophenyl)methylene]-2,4-imidazolidinedione (61%yield), m.p. >320° C.

Anal. Calcd. for C₁₃ H₁₃ N₃ O₄ : C, 56.73; H, 4.76; N, 15.27. Found: C,56.90; H, 4.73; N, 15.20.

NMR (DMSO-d₆): delta 3.83 (3H, s, OCHHD 3), 3.90 (3H, s, OCHHD 3), 3.95(3H, s, OCHHD 3), 7.08 (1H, s, aromatic H0 ortho to OCHHD 3). 7.51 (1H,s, aromatic H0 ortho to NCO), 10.89 (1H, s, NH 11.42 (1H, s, NH.

EXAMPLE 251,3-Dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quinolin-2-ones##STR52## (a)2-(Methylthio)-6-(trifluoromethyl)-1H-imidazo[4,5-b]quinolin

A suspension of1,3-dihydro-6-(trifluoromethyl)-2H-imdazo[4,5-b]quinolin-2-thione (0.53g, 2 mmol) in methanol (5 mL) was treated with 50% aqueous sodiumhydroxide (0.18 g) to afford a solution which was cooled in an ice bath.Methyl iodide (0.3 g, 0.13 mL, 2.1 mmol) was added and the mixturestirred for 90 minutes before being filtered. The solid was washed withmethanol and dried in air to give2-(methylthio)-6-(trifluoromethyl)-1H-imidazo[4,5-b]quinoline (0.34 g,61%), m.p. >270° C.

Anal. Calcd. for C₁₂ H₈ F₃ N₃ S: C, 50.88; H, 2.85; N, 14.83. Found: C,50.50; H, 2.83; N, 15.01.

NMR (DMSO-d₆): delta 2.81 (3H, s, S--CH₃), 7.70 (1H, dd, J=8.5 Hz, J'=2Hz, aromatic H0 ortho to CF₃), 8.29 (2H, m, aromatic H, 8.46 (1H, s,aromatic H0 ortho to N--C--SMe) and 13.30 (1H, bs, NH.

(b) 1,3-Dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quinolin-2-one

A mixture of2-(methylthio)-6-(trifluoromethyl)-1H-imidazo[4,5-b]quinoline (1.77 g, 6mmol), acetic acid (25 mL) and 3N hydrochloric acid solution (25 mL) washeated on a steam bath for 4 hours. The solution was diluted with hotwater (250 mL), cooled and filtered. The filtrate was concentrated toafford a second crop. Solids were combined with acetic acid (25 mL) and3N hydrochloric acid solution (25 mL) and the mixture heated on a steambath overnight. The mixture was diluted with hot water (250 mL), cooled,the solid collected and dried in vacuo to accord1,3-dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quinolin-2-one (1.38 g,83%), m.p. >250° C.

Anal. Calcd. for C₁₁ H₆ F₃ N₃ O: C, 52.18; H, 2.39; N, 16.60. Found: C,52.04; H, 2.43; N, 16.64.

EXAMPLE 26 1,3-Dihydro-1,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one##STR53##

This compound obtained as a partially hydrated hydrochloride salt wasprepared analogous to Example 7b from1-methyl-5-[(2-methyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione(49% yield), m.p. 340°-341° C. (dec.).

Anal. Calcd. for C₁₂ H₁₁ N₃ O.HCl.0.1H₂ O: C, 57.31; H, 4.89; N, 16.71.Found: C, 57.11; H, 4.75; N, 16.57.

NMR (DMSO-d₆): delta 2.66 (3H, s, aromatic CHHD 3), 3.41 (3H, s, N--CHHD3), 7.29 (1H, d, J=7 Hz, aromatic H0 ortho to CHHD 3), 7.45 (1H, t, J=7Hz, aromatic H0 meta to CHHD 3), 7.71 (1H, d, J=7 Hz, aromatic H0 parato CHHD 3), 7.87 (1H, s, aromatic H0 ortho to NH.CO).

EXAMPLE 27 1,3-Dihydro-1,7-dimethyl-2H-imidazo[4,5-b]quinolin-2-one##STR54##

This compound is prepared analogous to Example 7b from1-methyl-5-[(5-methyl-2-nitrophenyl)methylene]-2,4-imidazolidinedione,(46% yield), m.p. >320° C.

Anal. Calcd. for C₁₂ H₁₁ N₃ O.0.04H₂ O: C, 67.36; H, 5.22; N, 19.63.Found: C, 67.04; H, 5.21; N, 19.64.

NMR (DMSO-d₆): delta 2.46 (3H, s, aromatic CHHD 3), 3.35 (3H, s, N--CHHD3), 7.35 (1H, d, J=7 Hz, aromatic H0 ortho to CHHD 3), 7.62 (1H, s,aromatic H, 7.65 (1H, s, aromatic H, 7.70 (1H, d, J=7 Hz, aromatic H0meta to CHHD 3).

EXAMPLE 281,3-Dihydro-7-Methoxy-1-methyl-2H-imidazo[4,5-b]quinolin-2-one ##STR55##

This compound obtained as a partial hydrate was prepared analogous toExample 7b from5-[(5-methoxy-2-nitrophenyl)methylene]-1-methyl-2,4-imidazolidinedione,(54% yield), m.p. >310° C.

Anal. Calcd. for C₁₂ H₁₁ N₃ O₂ 0.02H₂ O: C, 62.77; H, 4.85; N, 18.30, H₂O, 0.157. Found: C, 62.43; H, 4.85; N, 18.14, H₂ O, 0.094.

NMR (DMSO-d₆): delta 3.34 (3H, s, NCHHD 3), 3.86 (3H, s, OCHHD 3), 7.18(1H, d, J=9 Hz, aromatic H0 ortho to OCHHD 3), 7.30 (1H, s, aromatic H0ortho to OCHHD 3), 7.66 (1H, s, aromatic H s, ortho to NHCO), 7.71 (1H,d, J=9 Hz, aromatic H0 meta to OCHHD 3).

EXAMPLE 29 1,3-Dihydro-1,7,8-trimethyl-2H-imidazo[4,5-b]quinolin-2-one##STR56##

This compound was prepared analogous to Example 7b from5-[(2,3-dimethyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione, (73%yield), m.p. >300° C. (crystallized from dimethylacetamide).

Anal. Calcd. for C₁₃ H₁₃ N₃ O: C, 68.70; H, 5.77; N, 18.49. Found: C,68.36; H, 5.78; N, 18.46.

NMR (DMSO-d₆): delta 2.42 (3H, s, CHHD 3), 2.55 (3H, s, CHHD 3), 3.39(3H, s, N--CHHD 3), 7.34 (1H, d, J=8.5 Hz, aromatic H0 ortho to CHHD 3),7.57 (1H, d, J=8.5 Hz, aromatic H0 meta to CHHD 3), 7.86 (1H, s,aromatic H0 ortho to NCO), 11.62 (1H, s, NH.

EXAMPLE 30 Method D. Preparation of hydantoin intermediate of FormulaXIII wherein a and b together form a covalent bond by reaction ofsubstituted 2-nitrobenzaldehydes of Formula IX' (IX; 4-R₁, 5-R₂, 6-R₃)with a hydantoin-5-phosphonate ##STR57## (a)5-[(2,3-Dimethyl-6-nitrophenyl)methylene]-2,3-imidazolidinedione (R₁ =R₄=H, R₂ =R₃ =CH₃)

Sodium (0.41 g, 0.018 g atom) was dissolved in ethanol (40 mL) anddiethyl 2,4-dioxoimidazolidine-5-phosphonate (4.21 g, 18 mmol) added.After 5 minutes, 2,3-dimethyl-6-nitrobenzaldehyde (2.66 g, 15 mmol) wasadded in one portion and the mixture stirred at room temperature for 90minutes. The mixture was diluted with water, filtered and the solidwashed with water and air dried gave5-[(2,3-dimethyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione as asingle geometrical isomer (3.35 g, 86%). Analytical sample prepared bycrystallization from methanol had m.p. 293°-295° C.

Anal. Calcd. for C₁₂ H₁₁ N₃ O₄ : C, 55.17; H, 4.24; N, 16.09. Found: C,54.97; H, 4.27; N, 16.09.

NMR (DMSO-d₆): delta 2.20 (3H, s, CH₃), 2.37 (3H, s, CH₃), 6.62 (1H, s,vinyl H), 7.39 (1H, d, J=9 Hz, aromatic H).

After standing overnight, a second crop consisting of a 1.1 mixture ofgeometrical isomers was collected from the aqueous layer (0.5 g, 12%),m.p. 267°-270° C. (dec.).

NMR (DMSO-d₆): delta 2.20 (6H, s), 2.33 (3H, s), 2.37 (3H, s), 6.45 (1H,s, vinyl H0 trans to C═O), 6.62 (1H, s, vinyl H0 cis to C═O), 7.31 (1H,d, J=8 Hz), 7.38 (1H, d, J=8 Hz), 7.73 (1H, d, J=8 Hz), 7.81 (1H, d, J=8Hz).

(b) 5-[(2-Methyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione (R₁ =R₂=R₄ =H; R₃ =CH₃)

Reaction of 2-methyl-6-nitrobenzaldehyde with diethyl2,4-dioxoimidazolidine-5-phosphate according to the procedure of MethodD provided the title compound as a single geometrical isomer, m.p.238°-239° C. (dec.) in 81% yield.

Anal. Calcd. for C₁₁ H₉ N₃ O₄ : C, 53.45; H, 3.67; N, 17.00. Found: C,53.44; H, 3.66; N, 16.92.

(c)5-[(2,3-Dimethyl-6-nitrophenyl)methylene]-1-methyl-2,4-imidazolidinedione(R₁ =H; R₂ =R₃ =R₄ =CH₃)

Reaction of 2,3-dimethyl-6nitrobenzaldehyde with diethyl1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to the procedureof Method D provided the title compound (partial hydrate) as a mixtureof geometrical isomers, m.p. 195°-198° C. in 88% yield.

Anal. Calcd. for C₁₃ H₁₃ N₃ O₄.0.1H₂ O: C, 56.36; H, 4.81; N, 15.17, H₂O, 0.65. Found: C, 56.38; H, 4.87; N, 14.54, H₂ O, 0.16.

(d)5-[(5-Methoxy-2-nitrophenyl)methylene]-1-methyl-2,4-imidazolidinedione(R₁ =R₃ =H; R₂ =OCH₃ ; R₄ =CH₃)

Reaction of 3-methoxy-6-nitrobenzaldehyde with diethyl1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to the procedureof Method D provided the title compound as a mixture of geometricalisomers, m.p. 257°-260° C. in 93% yield.

Anal. Calcd. for C₁₂ H₁₁ N₃ O₅ : C, 51.99; H, 4.00; N, 15.16. Found: C,51,87; H, 4.01; N, 14.90.

(e)1-Methyl-5-[(5-methyl-2-nitrophenyl)methylene]-2,4-imidazolidinedione(R₁ =R₃ =H; R₂ =R₄ =CH₃)

Reaction of 2-methyl-6-nitrobenzaldehyde with diethyl1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to procedure ofMethod D provided the title compound (partial hydrate) as a mixture ofgeometrical isomers, m.p. 261°-262° C. in 66% yield.

Anal. Calcd. for C₁₂ H₁₁ N₃ O₄.0.1H₂ O: C, 54.97; H, 4.29; N, 15.97; H₂O, 0.68. Found: C, 54,73; H, 4.30; N, 15.62; H₂ O, 0.24.

(f) 5-[4,5,6-Trimethoxy-2-nitrophenyl)methylene]-2,4-imidazolidinedione(R₁ =R₂ =R₃ =OCH₃ ; R₄ =H)

Reaction of 2,3,4-trimethoxy-6-nitrobenzaldehyde with diethyl2,4-dioxoimidazolidine-5-phosphonate according to procedure D providesthe title compound as a single geometrical isomer, m.p. 206°-208° C. in91% yield.

Anal. Calcd. for C₁₃ H₁₃ N₃ O₇ : C 48.30; H, 4.05; N, 13.00. Found: C,48.38; H, 4.02; N, 13.00.

(g)1-Methyl-5-[(2-methyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione(R₁ =R₂ =H; R₃ =R₄ =CH₃)

Reaction of 2-methyl-6-nitrobenzaldehyde with diethyl1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to procedure Dprovides the title compound as a mixture of geometrical isomers, m.p.194°-197° C. in 80% yield.

Anal. Calcd. for C₁₂ H₁₁ N₃ O₄ : C, 55.18; H, 4.25; N, 16.09. Found: C,54.94; H, 4.24; N, 15.82.

EXAMPLE 31 Method E. Preparation imidazo[4,5-b]quinolin-2-thiones ofFormula XIV ##STR58## (a)1,3-Dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quinolin-2-thione (XIV,R₁ =6-CF₃, R₂ =R₃ =R₄ =H)

Step 1.1,1-Dimethyl-[2-[(5-oxo-2-thioxo-4-imidazolidinylidene)methyl]-5-(trifluoromethyl)phenyl]carbamate.

A mixture of1,1-dimethylethyl[2-formyl-5-(trifluoromethyl)phenyl]carbamate (20 g, 60mmol) and 2-thiohydantoin (8.02 g, 60 mmol), ethanol (60 mL), water (60mL) and morpholine (6 mL) was heated on a steam bath. After 90 minutes,the mixture was cooled, allowed to stand overnight and the precipitatefiltered off and dried in vacuo to afford1,1-dimethyl[2-[5-oxo-2-thioxo-4-imidazolidinylidene]methyl]-5-[(trifluoromethyl)phenyl]carbamate(20.65 g, 77%), m.p. 216° C. (dec.).

Anal. Calcd. for C₁₆ H₁₆ F₃ N₃ O₃ S: C, 49.60; H, 4.16; N, 10.85; S,8.27. Found: C, 49.56; H, 4.10; N, 10.92; S, 7.96.

Step 2.5-[[2-Amino-4-(trifluormethyl)phenyl]methylene]-2-thioxo-4-imidazolidinone

Trifluoroacetic acid (90 mL) was added to a mixture of1,1-dimethylethyl[2-[(5-oxo-2-thioxo-4-imidazolidinylidene)methyl]-5-(trofluoromethyl)phenylcarbamate(18 g, 46 mmol) and anisole (36 g, 0.3 mole). When solution occurred,the solvent was evaporated and the residue crystallized from a mixtureof ethanol (65 mL) and chloroform (135 mL) to give5-[[2-amino-4-(trifluoromethyl)phenyl]methylene]-2-thioxo-4-imidazolidinone(9.85 g, 73%), m.p. 240° C.

Anal. Calcd. for C₁₁ H₁₈ F₃ N₃ OS: C, 45.99; H, 2.81; N, 14.63. Found:C, 46.00; H, 2.81; N, 14.54.

Step 3.1,3-Dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quinolin-2-thione.

A mixture of5-[[2-amino-4-(trifluoromethyl)phenyl]methylene]-2-thioxo-4-imidazolidinone(3.63 g, 12 mmol), pyridinium tosylate (1.8 g), and diphenyl ether (5.4g) was heated at 180° C. under an atmosphere of argon. After 18 minutes,the mixture was cooled, chloroform (60 mL) added and the mixturerefluxed. After 30 minutes the solid was filtered off and dissolved in amixture of water (80 mL) and 10% sodium hydroxide solution (5 mL) withwarming. Addition of acetic acid afforded a heavy precipitate which wasfiltered off, washed with water and dried in vacuo to give1,3-dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quinolin-2-thione (1.79g, 52%), m.p. >320° C.

Anal. Calcd. for C₁₁ H₆ F₃ N₃ S: C, 49.07; H, 2.25; N 15.61. Found: C,48.92; H, 2.23; N, 15.58.

(b) 1,3-Dihydro-7,8-dimethyl- 2H-imidazo[ 4,5-b]quinolin-2thione (XIV,R₁ =R₄ =H, R₂ =7-CH₃, R₃ =8-CH₃)

Prepared according to Method E by substituting2-amino-5,6-dimethylbenzaldehyde for 2-amino-4-trifluorobenzaldehyde asdescribed above in preparation of Example 31(a).

EXAMPLE 32 2,3-Dimethyl-6-nitrobenzaldehyde

Step 1. 2,3-Dimethyl-6-nitrobenzylamine.

A solution of borane-tetrahydrofuran complex (94.6 g, 1.1 mole) intetrahydrofuran (1100 mL) was added dropwise to a stirred solution of2,3-dimethyl-6-nitrobenzonitrile (96 g, 0.55 mole) in drytetrahydrofuran (650 mL) maintained under an atmosphere of argon. Afterstirring overnight, 10% hydrochloric acid solution (1300 mL) was addeddropwise and the mixture heated to reflux. After 30 minutes, thetetrahydrofuran was distilled off, the residue filtered to removeinsoluble material and the filtrate made basic with concentratedammonium hydroxide solution (350 mL). The mixture was extracted withdiethyl ether (2×500 mL), the combined extracts washed with water (2×400mL), dried over potassium carbonate and concentrated to afford2,3-dimethyl-6-nitrobenzyl amine (93.85 g, 95%) as an oil used withoutfurther purification as follows.

Step 2. 2,3-Dimethyl-6-nitrobenzenemethanol.

Sodium nitrite (36.5 g, 0.53 mole) in water (125 ml) was added dropwiseto a stirred mixture of 2,3-dimethyl-6-nitrobenzylamine (63.5 g, 0.35mole), acetic acid (165 mL) and water (165 mL) cooled in an ice bath.After completing the addition, the mixture was stirred for 10 minutes,warmed to room temperature and stirred to a further 10 minutes beforebeing diluted with water (1000 mL). The mixture was extracted withdichloromethane (3×500 mL), the combined extracts dried over magnesiumsulfate and concentrated to afford an oil which was dissolved inmethanol (400 mL). 1N Sodium hydroxide solution (400 mL) was addeddropwise over 20 minutes. The methanol was removed under reducedpressure, and the residue diluted with water (1200 mL) and extractedwith dichloromethane (3×700 mL). The combined extracts were dried overmagnesium sulfate and the solvent evaporated to afford2,3-dimethyl-6-nitrobenzyl alcohol (59.3 g, 93%) as brown solid used inStep 3 below without further purification. An analytical sample wasprepared by crystallization from hexane/diethyl ether, m.p. 48°-51° C.

Anal. Calcd. for C₉ H₁₁ NO₃ : C, 59.66; H, 6.12; N, 7.73. Found: C,59.72; H, 6.14; N, 7.67.

Step 3. 2,3-Dimethyl-6-nitrobenzaldehyde.

A solution of 2,3-dimethyl-6-nitrobenzenemethanol (34.88 g, 0.192 mole)in dichloromethane (150 mL) was added to a stirred mixture of pyridiniumchlorochromate (62.2 g, 0.288 mole) in dichloromethane (250 ml). Themixture was stirred vigorously for 4 hours, diluted with diethyl ether(500 mL) and the organic layer decanted. The residue was washed withdiethyl ether (500 mL) and the combined organic solution filteredthrough a plug of silica gel (6"×11/2"). Evaporation of the solventafforded 2,3-dimethyl-6-nitrobenzaldehyde (32.08 g, 93%). An analyticalsample was prepared by crystallizing from diisopropyl ether and had m.p.66°-68° C.

Anal. Calcd. for C₉ H₉ NO₃ : C, 60.33; H, 5.06; N, 7.82. Found: C,60.19; H, 5.27; N, 8.27.

EXAMPLE 335-[((6-Amino-2,3-dimethyl)phenyl)methyl]-2,4-imidazolidinedione

5-[(2,3-Dimethyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione (2.40g, 9.2 mmol) in dimethylformamide (40 mL) was hydrogenated over 10%palladium on charcoal (0.24 g) at 60 p.s.i. in a Parr hydrogenationapparatus. After 18 hours, the mixture was filtered through infusorialearth and the solvent evaporated in vacuo at 40° C. to give thepreviously disclosed (Example 19-7)5-[(6-amino-2,3-dimethylphenyl)methyl]-2,4-imidazolidinedione as apartial hydrate (2.04 g, 100%), as khaki solid, m.p. >360° C.

Anal. Calcd. for C₁₂ H₁₅ N₃ O₂.0.3H₂ O: C, 60.76; H, 6.60; N, 17.35; H₂O, 2.82. Found: C, 60.39; H, 6.59; N, 17.61; H₂ O, 2.26.

EXAMPLE 341-Methyl-5-[(2-amino-6-methylphenyl)methyl]-2,4-imidazolidinedione

Prepared from1-methyl-5-[(2-methyl-6-nitrophenyl)methylene]-2,4-imidazolidinedioneaccording to the procedure of Example 19.

EXAMPLE 357,8-Dimethyl-1,3,9,9a-tetrahydro-2H-imidazo-[4,5-b]quinolin-2-one##STR59##

A mixture of5-[(6-amino-2,3-dimethylphenyl)methyl]-2,4-imidazolidinedione (2.52 g,10 mmol), p-toluenesulfonic acid (0.25 g) and methanol (50 mL) wasrefluxed under an atmosphere of argon for 1 hour. The mixture was cooledand a grey solid filtered off and dissolved in 10% hydrogen chloride inmethanol with warming. Addition of ether afforded the previouslydisclosed7,8-dimethyl-1,3,9,9a-tetrahydro-2H-imidazo[4,5-b]quinolin-2-one(Example 20-7) as the hydrochloride (1.68 g, 87%), m.p. >230° C.

Anal. Calcd. for C₁₂ H₁₃ N₃ O.HCl: C, 57.26; H, 5.61; N, 16.70. Found:C, 56.92; H, 5.48; N, 16.44.

NMR (DMSO-d₆): delta 2.20 (3H, s, C₃), 2.27 (3H, s, C₃), 2.80 (1H, t,J=14 Hz, benzylic H, 3.34 (1H, dd, J=14 Hz, J'=8 Hz, benzylic H, 4.84(1H, dd, J=14 Hz, J'=8 Hz, CHCO), 7.18 (1H, d, J=9 Hz, aromatic H, 7.31(1H, d, J=8 Hz, aromatic H and 9.22 (2H, s, NH).

EXAMPLE 361,3,9,9a-Tetrahydro-1,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one##STR60##

Prepared from1-methyl-5-[(2-amino-6-methylphenyl)methyl]-2,4-imidazolidine accordingto the procedure of Example 20, m.p. 340°-345° C. (dec.).

Anal. Calcd. for C₁₂ H₁₃ N₃ O.HCl: C, 57.27; H, 5.61; N, 16.70. Found:C, 57.47; H, 5.55; N, 16.64.

EXAMPLE 37 1,3-Dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one##STR61##

5-[(2,3-Dimethyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione (19.95g, 76 mmol) in dimethylformamide (350 mL) was hydrogenated over 10%palladium on charcoal (3 g) at 60 p.s.i. in a Parr hydrogenationapparatus. After hydrogen uptake ceased, the mixture was filteredthrough kieselgehr and the solvent evaporated to leave a solid which wassuspended in a refluxing methanol (1 L). Iodine (19.4 g, 76 mmol) wasadded portionwise over 5 minutes and the mixture refluxed for 15 minutesbefore being concentrated in vacuo to about 100 mL. A solution of sodiumthiosulfate (21 g) and sodium carbonate (11 g) in water (300 mL) wasadded with vigorous stirring to afford a beige precipitate which wascollected, washed with water and dried in air to give 15.7 g. This wascombined with crude material from experiments performed on 40 g and 4.16g of starting material, suspended in hot (80° C.) water, filtered,suspended in refluxing methanol and filtered. Crystallization fromdimethylacetamide afforded1,3-dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one (53.4 g, 65%),m.p. >300° C.

Anal. Calcd. for C₁₂ H₁₁ N₃ O: C, 67.59; H, 5.20; N, 19.71. Found: C,67.28; H, 5.20; N, 19.51.

NMR (DMSO-d₆): delta 2.41 (3H, s, CH₃), 2.48 (3H, s, CH₃), 7.31 (1H, d,J=8 Hz, aromatic H, 7.55 (1H, d, J=8 Hz, aromatic H and 7.61 (1H, s,aromatic H.

EXAMPLE 38 5-[(5-Ethoxy-2-nitrophenyl)methylene]-2,4-imidazolidinedione

Reaction of 2-nitro-5-ethoxybenzaldehyde with imidazolidine-2-dioneaccording to the procedure of Method C (Example 18) provided the titlecompound as a single geometrical isomer, m.p. 243°-245° C. in 51% yield.

Anal. Calcd. for C₁₂ H₁₁ N₃ O₅ : C, 51.99; H, 4.00; N, 15.16. Found: C,51.78; H, 4,05; N, 14.91.

EXAMPLE 395-[[5-(1-Methylethoxy)-2-nitro]-methylene]-2,4-imidazolidinedione

Reaction of 2-nitro-5-(1-methylethoxy)-2-benzaldehyde according to theprocedure of Method C (Example 18) provided the title compound as asingle geometrical isomer, m.p. 223°-230° C. in 69% yield.

Anal. Calcd. for C₁₃ H₁₃ N₃ O₅ : C, 53.61; H, 4.50; N, 14.43. Found: C,53.55; H, 4.43; N, 14.25.

EXAMPLE 40 1,3-Dihydro-7-ethoxy-2H-imidazo[4,5-b]quinolin-2-one##STR62##

This compound (previously disclosed as Example 15-7) was preparedanalogous to Example 12 from5-[(5-ethoxy-2-nitrophenyl)methylene]-2,4-imidazolidinedione (43%),m.p. >320° C.

Anal. Calcd. for C₁₂ H₁₁ N₃ O₂ : C, 62.88; H, 4.84; N, 18.33. Found: C,62.68; H, 4.92; N, 18.16.

NMR (DMSO-d₆): delta 1.36 (3H, t, J=7 Hz, OCH₂ CH₃), 4.04 (2H, q, OCHHD2CH₃), 6.97 (1H, dd, J=9 Hz, J'=2.6 Hz, aromatic H0 ortho to OEt), 7.08(1H, d, J=2.6 Hz, aromatic H0 ortho to OEt), 7.26 (1H, s, aromatic H0ortho to NCO), 7.64 (1H, d, J=9 Hz, aromatic H0 meta to OEt).

EXAMPLE 411,1-Dimethylethyl-[2-formyl-5-(trifluoromethyl)phenyl]carbamate (a)1,1-Dimethylethyl-[5-(trifluoromethyl)phenyl]carbonate

A mixture of 3-aminobenzotrifluoride (16 g, 0.1 mole) anddi-tert-butyldicarbonate (32 g, 0.15 mole) and tetrahydrofuran (THF) (25mL) was stirred at room temperature for 90 minutes and then heat atreflux for 90 minutes. The mixture was diluted with water (10 mL),allowed to stand overnight and concentrated in vacuo. The residue wasdissolved in hexane (100 mL) at reflux, treated with activated carbon,filtered and cooled to 0° C. for 16 hours. Filtration afforded1,1-dimethylethyl-[5-(trifluoromethyl)phenyl]carbonate (75-80% yield onseveral runs), m.p. 75°-76° C.

Anal. Calcd. for C₁₂ H₁₄ F₃ NO₂ : C, 55.17; H, 5.40; N, 5,36. Found: C,55.13; H, 5.45; N, 5.33.

(b) 1,1-Dimethylethyl-[2-formyl-5-(trifluoromethyl)phenyl]carbamate

s-Butyllithium 15 mL of a 1.45M solution in THF (22 mmole) was addeddropwise to a stirred solution of1,1-dimethylethyl-[5-(trifluoromethyl)phenyl]carbonate (2.61 g, 10mmole) in dry THF (40 mL) maintained at -40° C. under an atmosphere ofargon. After 40 minutes, N,N-dimethylformamide (1.15 mL, 15 mmole) wasadded and the mixture stirred at -40° C. for 10 minutes before beingdiluted with diethyl ether (30 mL). The mixture was washed with 10%acetic acid solution (30 mL) and saturated sodium chloride solution (30mL), dried over magnesium sulfate and concentrated in vacuo. The residuewas chromatographed on a column of silica using a mixture of hexane andethyl acetate (95:5) as eluent to afford1,1-dimethylethyl-[2-formyl-5-(trifluoromethyl)phenyl]carbamate, yield70-84%.

Anal. Calcd. for C₁₃ H₁₄ F₃ NO₃ : C, 53.98; H, 4.87; N, 4.84. Found: C,53.67; H, 4.87; N, 4.85

EXAMPLE 42 Diethyl 1-Methyl-2,4-dioxoimidazolidine-5-phosphonate

A mixture of 1-methylimidazolidine-2,4-dione (202.5 g, 1.8M) and glacialacetic acid (1 L) was heated to 90° C. in an oil bath. An additionfunnel was charged with bromine (311.5 g, 100 mL, 1.95M) and a smallamount of bromine introduced into the reaction mixture. Afterdissipation of the orange color, the remainder of the bromine was addeddropwise at such a rate that instant decolorization occurred. Aftercompleting the addition, the mixture was stirred at 90° C. for 60minutes, cooled to room temperature and stirred overnight. The aceticacid was decanted from a white precipitate, concentrated in vacuo andthe residue combined with the precipitate and suspended in diethyl ether(approximately 2 L). Triethyl phosphite (295 g, 320 mL, 1.8M) was addedportionwise with stirring. An exothermic reaction ensued which wascontrolled with tap water cooling of the reaction vessel. A solutionresulted which, on continued stirring, yielded a white precipitate.After standing for 60 minutes the mixture was poured into diethyl ether(4 L) and allowed to stand overnight. Filtration affordeddiethyl-2-methyl-2,4-dioxoimidazolidine-5-phosphonate (331.7 g, 75%),m.p. 95°-96° C. An analytical sample crystallized from MeOH/Et₂ O hadm.p. 95°-96° C.

Anal. Calcd. for C₈ H₁₅ N₂ O₅ P: C, 38.41; H, 6.04; N, 11.20. Found:38.22; H, 6.07; N, 11.04.

The following 5-phosphonate hydantoin intermediates can be preparedanalogously by substituting the appropriate imidazolidine-2,4-dione for1-methylimidazolidine-2,4-dione in the above procedure:

diethyl 2,4-dioxoimidazolidine-5-phosphonate, m.p. 161°-163°crystallizedfrom ethanol,

diethyl 1-ethyl-2,4-dioxoimidazolidine-5-phosphonate,

diethyl 1-propyl-2,4-dioxoimidazolidine-5-phosphonate,

diethyl 1-isopropyl-2,4-dioxoimidazolidine-5-phosphonate,

diethyl 1-butyl-2,4-dioxoimidazolidine-5-phosphonate,

diethyl 1-iso-butyl-2,4-dioxoimidazolidine-5-phosphonate,

diethyl 1-tert-butyl-2,4-dioxoimidazolidine-5-phosphonate.

What is claimed is:
 1. A compound of the formula ##STR63## wherein R₁ ishalogen, lower alkyl, lower alkoxy, trifluoromethyl;R₂ is hydrogen,halogen, lower alkyl, lower alkoxy; R₃ is hydrogen, halogen, loweralkyl, lower alkoxy; R₄ is hydrogen, lower alkylor a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1 of the formula##STR64## R₁ is halogen, lower alkyl, lower alkoxy, trifluoromethyl; R₂is hydrogen, halogen, lower alkyl, lower alkoxy;R₃ is hydrogen, halogen,lower alkyl, lower alkoxy;or a pharmaceutically acceptable salt thereof.3. The compound of claim 1 or a pharmaceutically acceptable salt thereofwhich is 8-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one.
 4. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof whichis 7-fluoro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one.
 5. The compoundof claim 1 or a pharmaceutically acceptable salt thereof which is8-methyl-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one.
 6. The compound ofclaim 1 or a pharmaceutically acceptable salt thereof which is7-methyl-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one.
 7. The compound ofclaim 1 or a pharmaceutically acceptable salt thereof which is7-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one.
 8. The compound ofclaim 1 or a pharmaceutically acceptable salt thereof which is1,3-dihydro-6,7-dimethyl-2H-imidazo[4,5-b]quinolin-2-one.
 9. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof whichis 1,3-dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one.
 10. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof whichis 1,3-dihydro-7-chloro-6-methyl-2H-imidazo[4,5-b]quinolin-2-one. 11.The compound of claim 1 or a pharmaceutically acceptable salt thereofwhich is 1,3-dihydro-8methoxy-2H-imidazo[4,5-b]quinolin-2-one.
 12. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof whichis 1,3-dihydro-8-chloro-7-methyl-2H-imidazo[4,5-b]quinolin-2-one. 13.The compound of claim 1 or a pharmaceutically acceptable salt thereofwhich is7-chloro-1,3-dihydro-6,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one 14.The compound of claim 1 or a pharmaceutically acceptable salt thereofwhich is 7-methoxy-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one.
 15. Thecompound of claim 1 which is1,3-dihydro-6,7-dimethoxy-2H-imidazo[4,5-b]quinolin-2-one.
 16. Thecompound of claim 1 which is7-bromo-1,3-dihydro-6,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one. 17.The compound of claim 1 which is7-bromo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one.
 18. The compound ofclaim 1 which is1,3-dihydro-7-(1-methylethoxy)-2H-imidazo[4,5-b]quinolin-2-one.
 19. Thecompound of claim 1 which is1,3-dihydro-6,7,8-trimethoxy-2H-imidazo[4,5-b]quinolin-2-one.
 20. Thecompound of claim 1 which is1,3-dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quinolin-2-one.
 21. Thecompound of claim 1 which is1,3-dihydro-1,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one.
 22. Thecompound of claim 1 which is1,3dihydro-1,7-dimethyl-2H-imidazo[4,5-b]quinolin-2-one.
 23. Thecompound of claim 1 which is1,3-dihydro-7-methoxy-1-methyl-2H-imidazo[4,5-b]quinolin-2-one.
 24. Thecompound of claim 1 which is1,3-dihydro-1,7,8-trimethyl-2H-imidazo[4,5-b]quinolin-2-one.
 25. Thecompound of claim 1 which is1,3-dihydro-7-ethoxy-2H-imidazo[4,5-b]quinolin-2-one.
 26. A compound ofthe formula ##STR65## wherein R₁ is halogen, lower alkyl, lower alkoxy,trifluoromethyl; p1 R₂ is hydrogen, halogen, lower alkyl, loweralkoxy;R₃ is hydrogen, halogen, lower alkyl, lower alkoxy; R₄ ishydrogen, lower alkyl.
 27. The compound of claim 26 which is8-methyl-1,3,9,9a-tetrahydro-2H-imidazo[4,5-b]quinolin-2-one.
 28. Thecompound of claim 26 which is7,8-dimethyl-1,3,9,9a-tetrahydro-2H-imidazo[4,5-b]quinolin-2-one. 29.The compound of claim 26 which is1,3,9,9a-tetrahydro-1,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one.
 30. Acompound of the formula ##STR66## wherein R₁ is halogen, lower alkyl,lower alkoxy, trifluoromethyl;R₂ is hydrogen, halogen, lower alkyl,lower alkoxy; R₃ is hydrogen, halogen, lower alkyl, lower alkoxy; R₄ ishydrogen, lower alkylor a pharmaceutically acceptable salt thereof. 31.A method for inhibiting phosphodiesterase and blood platelet aggregationin a mammal which comprises administering a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof.
 32. A method for increasing heart inotropic activity whichcomprises administering to a warm blooded animal, in need of suchtreatment a therapeutically effective amount of a compound of claim 1 ora pharmaceutically acceptable salt thereof.
 33. The pharmaceuticalcomposition used in a method for inhibiting phosphodiesterase and bloodplatelet aggregation in a mammal comprised of a therapeuticallyeffective amount in dosage unit form of a compound of claim 1 or apharmaceutically acceptable acid addition salt thereof and apharmaceutical carrier.
 34. The pharmaceutical composition used in amethod for increasing heart inotropic activity in a warm blooded animalcomprised of a therapeutically effective amount in dosage unit form of acompound of claim 1 or a pharmaceutically acceptable acid addition saltthereof and a pharmaceutical carrier.